Assuntos
Obstrução das Vias Respiratórias/terapia , Epidermólise Bolhosa Adquirida/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Doenças da Laringe/terapia , Doenças Faríngeas/terapia , Obstrução das Vias Respiratórias/complicações , Epidermólise Bolhosa Adquirida/complicações , Humanos , Doenças da Laringe/complicações , Masculino , Pessoa de Meia-Idade , Doenças Faríngeas/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. METHODS: Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment. RESULTS: Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). CONCLUSIONS: Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough.
Assuntos
Asma/complicações , Tosse/etiologia , Administração por Inalação , Corticosteroides/uso terapêutico , Adulto , Idoso , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Resistência a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Background: Cough is a common feature of asthma, which is often resistant to inhaled corticosteroids (ICSs). The pathophysiology of this refractoriness may differ between daytime and nighttime asthmatic cough. We sought to identify factors contributing to ICS-refractory daytime and nighttime asthmatic cough. Methods: Sixty-seven patients with asthma presenting solely or predominantly with chronic cough were prospectively enrolled from April 2012 to December 2014. At baseline and 12 weeks after ICS treatment, the capsaicin cough threshold (C2, C5) and methacholine airway sensitivity and reactivity were examined. A visual analog scale (VAS) and numeric scores were used to evaluate daytime and nighttime cough symptoms separately. The Japanese version of the Leicester Cough Questionnaire was also completed. When either the VAS or numeric scores showed an improvement of ≥50% or ≥2 points, patients were considered responders to ICS treatment.Results: Fifty-five patients were eligible for evaluation. Subjective cough indices improved significantly at 12 weeks after ICS treatment (P<.001). Multivariate analysis revealed that lower C2 significantly contributed to residual daytime cough (P=.04). Meanwhile, methacholine hyperreactivity and lower IgE levels were predictors of the nighttime residual cough (P=.002 and P=.03, respectively). Conclusions: Heightened cough reflex sensitivity is an independent factor of daytime asthmatic cough that is refractory to ICSs. In contrast, airway hyperreactivity and less atopic status contribute to ICS-refractory nighttime cough
Introducción: La tos es una característica común del asma, que a menudo es resistente a los corticosteroides inhalados (ICS). La fisiopatología involucrada en dicha refractariedad al tratamiento esteroideo puede ser diferente entre la tos asmática diurna y nocturna. El objetivo del estudio es intentar identificar los factores que contribuyen a esta insensibilidad al tratamiento en la tos asmática diurna y nocturna. Métodos: Sesenta y siete pacientes, con asma solo o con tos crónica, se inscribieron prospectivamente desde abril de 2012 a diciembre de 2014. Al inicio del estudio y 12 semanas después del tratamiento con ICS, se examinaron el umbral de tos frente a capsaicina (C2, C5) y la sensibilidad y reactividad de las vías respiratorias a la metacolina. Se usaron escalas analógicas visuales (VAS) y puntajes numéricos para evaluar los síntomas de tos diurna y nocturna de forma separada. La versión japonesa del Leicester Cough Questionnaire también se completó. Cuando las VAS o los puntajes numéricos mostraron una mejoría de ≥50% o ≥2 puntos, los pacientes se consideraron respondedores al tratamiento con ICS. Resultados: Cincuenta y cinco pacientes completaron adecuadamente toda la evaluación. Los índices subjetivos de tos mejoraron significativamente a las 12 semanas después del tratamiento con ICS (p <0,001). El análisis multivariante reveló que una C2 más baja contribuía significativamente a la tos diurna residual (p = 0,04). Por otra parte, la hiperreactividad a la metacolina y los niveles más bajos de IgE fueron predictores de la tos residual nocturna (p = 0,002 y p = 0,03, respectivamente).Conclusiones: La sensibilidad aumentada a la tos es un factor independiente de la tos asmática diurna refractaria a los corticoides. Por el contrario, la hiperreactividad de las vías respiratorias y la ausencia de atopia contribuyen a la tos nocturna refractaria a los ICS
Assuntos
Humanos , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Rinite Alérgica/imunologia , Hipersensibilidade Imediata/imunologia , Corticosteroides/administração & dosagem , Administração por Inalação , Testes de Função Respiratória/estatística & dados numéricos , Tosse/imunologia , Asma/imunologiaRESUMO
BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.
Assuntos
Proteínas ADAM , Asma/sangue , Asma/genética , Subunidade alfa de Receptor de Interleucina-4 , Proteínas ADAM/sangue , Proteínas ADAM/genética , Adulto , Idoso , Asma/tratamento farmacológico , Seguimentos , Marcadores Genéticos , Humanos , Subunidade alfa de Receptor de Interleucina-4/sangue , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.
Assuntos
Antiasmáticos/uso terapêutico , Asma/sangue , Asma/tratamento farmacológico , Moléculas de Adesão Celular/sangue , Imunoglobulina E/sangue , Omalizumab/uso terapêutico , Adulto , Idoso , Antiasmáticos/farmacologia , Asma/diagnóstico , Asma/imunologia , Biomarcadores , Progressão da Doença , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Omalizumab/farmacologia , Curva ROC , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.
Assuntos
Asma/epidemiologia , Asma/etiologia , Respiração Bucal , Adulto , Idoso , Asma/diagnóstico , Biomarcadores , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Morbidade , Razão de Chances , Vigilância da População , Testes de Função Respiratória , Fatores de Risco , AutorrelatoRESUMO
BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
Assuntos
Asma/genética , Asma/fisiopatologia , Variação Genética , Receptores de Glucocorticoides/genética , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Idoso , Asma/tratamento farmacológico , Asma/imunologia , Moléculas de Adesão Celular/sangue , Eosinófilos/imunologia , Feminino , Volume Expiratório Forçado , Estudos de Associação Genética , Proteínas de Choque Térmico/genética , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de RiscoRESUMO
BACKGROUND: Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown. OBJECTIVE: To determine the effects of smoking on serum immunoglobulin E (IgE) levels and eosinophilic inflammation in asthmatics of all ages. METHODS: The associations of serum IgE levels, blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels with smoking and age in steroid-naive asthmatics were cross-sectionally assessed (n = 307). Levels of sputum eosinophil and thymic stromal lymphopoietin (TSLP) that promotes Th2 inflammation were also analysed. Current smokers were excluded when analysing contributing factors of FeNO. RESULTS: Levels of serum IgE, blood eosinophil and FeNO decreased with increasing age in never-smokers, whereas decrease in serum IgE levels with increasing age was not observed in current smokers. In addition, current smoking was associated with higher blood eosinophil counts. In atopic asthmatics, age-related declines in serum IgE levels were less steep in ex-smokers than in never-smokers, and atopic ex-smokers with asthma showed higher blood eosinophil counts and higher FeNO irrespective of age. Lastly, sputum TSLP levels were associated with sputum eosinophil proportions and pack-years. Current and ex-smokers had higher TSLP levels than never-smokers. CONCLUSIONS AND CLINICAL RELEVANCE: In steroid-naive asthmatics, smoking may attenuate the age-related decrease in IgE levels and maintain eosinophilic inflammation, in which TSLP may be involved.
Assuntos
Eosinófilos/imunologia , Imunoglobulina E/imunologia , Inflamação/imunologia , Fumar , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Asma/imunologia , Asma/metabolismo , Estudos Transversais , Citocinas/metabolismo , Expiração , Feminino , Compostos Férricos/sangue , Humanos , Imunoglobulina E/sangue , Inflamação/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Óxido Nítrico , Escarro/metabolismo , Adulto Jovem , Linfopoietina do Estroma do TimoRESUMO
BACKGROUND: Effects of long-term treatment with inhaled corticosteroids (ICSs) on airway-wall thickness in patients with asthma remain unknown. OBJECTIVES: To determine whether airway-wall thickness consistently decreases after long-term ICS treatment, and to analyze factors contributing to long-term airway-wall changes in asthmatics. METHODS: A retrospective analysis of long-term changes in airway-wall thickness using computed tomography was performed in 14 patients with asthma. Wall area corrected by body surface area (WA/BSA) was examined at baseline, 12 weeks after the commencement of ICSs (second measurement), and at least 2 years (mean +/- SEM. 4.2 +/- 0.5) after the second measurement (third measurement). Mean +/- SEM changes in WA/BSA from the second to the third measurements were analyzed. RESULTS: The mean change in WA/BSA was not significant between the second and the third measurements (-0.27 +/- 0.59 mm2/m2/y). Overall, the changes were significantly associated with disease duration but not with other clinical indices. When the 14 patients were divided into 2 groups using a cutoff value of 0.32 mm2/m2/y for the mean change in WA/BSA, for the 5 patients whose WA/BSA exceeded this cutoff, daily ICS doses were not reduced and both forced expiratory volume in the first second (FEV1) and forced vital capacity decreased significantly. For the remaining 9 patients, daily ICS doses were reduced and long-term FEV1 values did not change. CONCLUSIONS: Despite long-term treatment with ICSs, airway-wall thickness did not consistently decrease. One possible mechanism underlying poor response to long-term treatment may be long-standing asthma.
Assuntos
Corticosteroides/efeitos adversos , Asma/diagnóstico por imagem , Sistema Respiratório/patologia , Tomografia Computadorizada por Raios X , Administração por Inalação , Corticosteroides/uso terapêutico , Adulto , Idoso , Asma/tratamento farmacológico , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Sistema Respiratório/efeitos dos fármacos , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Isoprostanes are prostaglandin (PG)-like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated. OBJECTIVE: This study was designed to determine the intracellular mechanisms underlying the effects of oxidative stress on airway smooth muscle, focused on Ca(2+) signalling pathways involved in the effect of 8-iso-PGF(2 alpha). METHODS: Using simultaneous recording of isometric tension and F(340)/F(380) (an indicator of intracellular concentrations of Ca(2+), [Ca(2+)]i, we examined the correlation between tension and [Ca(2+)]i in response to 8-iso-PGF(2 alpha) in the fura-2 loaded tracheal smooth muscle. RESULTS: Augmented tension and F(340)/F(380) by 8-iso-PGF(2 alpha) were attenuated by ICI-192605, an antagonist of thromboxane A(2) receptors (TP receptors). Moreover, D609, an antagonist of phosphatidylcholine-specific phospholipase C, markedly reduced both the tension and F(340)/F(380) induced by 8-iso-PGF(2 alpha), whereas U73122, an antagonist of phosphatidylinositol-specific phospholipase C, modestly inhibited them by 8-iso-PGF(2 alpha). SKF96365, a non-selective antagonist of Ca(2+) channels, markedly reduced both tension and F(340)/F(380) by 8-iso-PGF(2 alpha). However, diltiazem and verapamil, voltage-dependent Ca(2+) channel inhibitors, modestly attenuated tension although their reduction of F(340)/F(380) was not different from that by SKF96365. Y-27632, an inhibitor of Rho-kinase, significantly attenuated contraction induced by 8-iso-PGF(2 alpha) without reducing F(340)/F(380), whereas GF109203X and Go6983, protein kinase C inhibitors, did not markedly antagonize them although reducing F(340)/F(380) with a potency similar to Y-27632. CONCLUSION: 8-iso-PGF(2 alpha) causes airway smooth muscle contraction via activation of TP receptors. Ca(2+) mobilization by SKF96365- and D609-sensitive Ca(2+) influx and Ca(2+) sensitization by Rho-kinase contribute to the intracellular mechanisms underlying the action of 8-iso-PGF(2 alpha). Rho-kinase may be a therapeutic target for the physiologic abnormalities induced by oxidative stress in airways.
Assuntos
Sinalização do Cálcio/fisiologia , Dinoprosta/análogos & derivados , Músculo Liso/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Amidas/farmacologia , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Diltiazem/farmacologia , Dinoprosta/farmacologia , Dioxanos/farmacologia , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Cobaias , Imidazóis/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Masculino , Maleimidas/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Norbornanos , Piridinas/farmacologia , Pirrolidinonas/farmacologia , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tiocarbamatos , Tionas/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Vasoconstritores/farmacologia , Verapamil/farmacologia , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
BACKGROUND: Transforming growth factor (TGF) beta1 is considered to play central roles in the pathogenesis of airway remodeling in asthma. This notion is based primarily on the results of experimental studies; clinical evidence is limited. OBJECTIVES: To ascertain the involvement of TGF-beta1 in asthma. METHODS: We studied 27 patients with moderate-to-severe, but stable, asthma treated with inhaled corticosteroids and 8 healthy controls. Helical computed tomography scans were acquired at full inspiration. Airway wall thickness (WT) was assessed on the basis of wall area corrected for body surface area (WA/BSA) and absolute WT corrected for BSA (WT/square root of BSA) according to a validated method. Induced sputum concentrations of TGF-beta1 were measured by enzyme-linked immunosorbent assay. Pulmonary function was evaluated. RESULTS: Indices of expiratory airflow were significantly lower in the asthmatic patients than in the controls. WA/BSA, WT/square root of square root of BSA, and sputum concentrations of TGF-beta1 were significantly higher in the asthmatic patients. Sputum TGF-beta1 concentrations correlated positively with WA/BSA and WT/square root of BSA and negatively with forced expiratory volume in 1 second in both asthmatic and control subjects. CONCLUSIONS: Levels of TGF-beta1 in induced sputum are elevated in asthmatic patients despite treatment with inhaled corticosteroids and are associated with airflow obstruction and airway wall thickening. TGF-beta1 is involved in the pathogenesis of airway remodeling and resultant functional impairment and it may be a target for specific medical treatment.
Assuntos
Corticosteroides/uso terapêutico , Asma/metabolismo , Escarro/química , Fator de Crescimento Transformador beta1/análise , Adulto , Idoso , Antiasmáticos/uso terapêutico , Asma/diagnóstico por imagem , Asma/tratamento farmacológico , Asma/patologia , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada EspiralRESUMO
BACKGROUND: Recent studies have revealed that in asthma, mast cells infiltrate to the smooth muscle layer and release tryptase, an enzymatic activator of protease-activated receptor 2 (PAR2). This phenomenon, mast cell myositis, is proposed as a new feature of asthma. However, little is known about the involvement of mast cell myositis in the pathophysiology of asthma. OBJECTIVE: This study was designed to determine whether mast cell degranulation has any functional impact on beta-adrenoceptors via PAR2 in airway smooth muscle. Moreover, we focused on Ca(2+) signalling as a mechanism underlying alteration of smooth muscle tone and responsiveness. METHODS: Isometric tension and F(340)/F(380), an indicator of the concentration of intracellular Ca(2+) ([Ca(2+)](i)), were simultaneously measured using fura-2-loaded tissues isolated from guinea-pig tracheal smooth muscle. RESULTS: Tryptase (1-100 nm) caused tension with elevated F(340)/F(380), and after exposure to tryptase for 15 min the inhibitory effect of isoprenaline (ISO) against methacholine was attenuated without elevating F(340)/F(380) in a concentration-dependent manner. Tryptase (<1 nm) had a modest effect on tension, but prolonged treatment (=120 min) with 0.1 nm tryptase also reduced the effects of ISO in a time-dependent manner. When tissues were incubated with tryptase in the presence of Y-27632, a Rho-kinase inhibitor, reduced responsiveness to ISO by tryptase was reversed without affecting F(340)/F(380). In contrast, pre-treatment with SKF96365, a non-selective inhibitor of Ca(2+) channels, did not antagonize the effect of tryptase. Moreover, pre-treatment with SLIGKV-NH(2), a non-enzymatic activator of PAR2, resulted in a loss of beta-adrenergic efficacy, similar to tryptase. The effect of cAMP-related agents bypassing beta-adrenoceptors was not attenuated after exposure to tryptase. CONCLUSION: In mast cell myositis, tryptase released from mast cells acts on airway smooth muscle, leading to homologous beta-adrenergic desensitization mediated by [Ca(2+)](i)-independent mechanisms via PAR2 activation.
Assuntos
Cálcio/metabolismo , Mastócitos/enzimologia , Músculo Liso/metabolismo , Receptores Adrenérgicos beta/metabolismo , Traqueia/metabolismo , Triptases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cobaias , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Receptor PAR-2/metabolismo , Traqueia/efeitos dos fármacos , Quinases Associadas a rho/metabolismoRESUMO
BACKGROUND: The release of adenosine triphosphate (ATP) from the airway epithelial cells during the inflammatory process is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. OBJECTIVE: This study was designed to determine whether extracellular ATP is involved in the bronchial hyperresponsiveness as an interaction between epithelium and smooth muscle in the airways. METHODS: We examined the contractile response to methacholine (MCh) before and after exposure to low concentrations (< or = 10 microm) of ATP in isolated, epithelium-denuded guinea-pig tracheal smooth muscle by measuring isometric tension. Intracellular Ca2+ concentrations ([Ca2+]i) were assessed by fluorescent intensities of fura-2. RESULTS: MCh-induced contractile force was increased with no change in [Ca2+]i after exposure to 10 microm ATP for 15 min. The ability of ATP to enhance the MCh-induced contraction was markedly attenuated by suramin, a non-selective P2 receptor inhibitor. Pre-incubation with ATPgammaS, a non-hydrolysable analogue of ATP and alpha,beta-meATP, a P2X agonist, also enhanced the MCh-induced contraction. In contrast, uracil triphosphate, a P2Y agonist, did not affect the MCh-induced contraction. Y-27632, a Rho-kinase inhibitor, suppressed the ability of ATP to enhance the MCh-induced contraction. Moreover, PP1 and PP2, Src tyrosin kinase inhibitors, suppressed the enhancement of MCh-induced contraction by ATP. CONCLUSION: Pre-treatment with ATP induces hyperresponsiveness to MCh mediated by Ca2+ sensitization via the P2X receptor in airway smooth muscle. The present findings suggest the possible involvement of both the Rho-kinase and Src pathways in the intracellular mechanism of this phenomenon.
Assuntos
Trifosfato de Adenosina/farmacologia , Brônquios/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Sinalização do Cálcio , Miócitos de Músculo Liso/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Agonistas do Receptor Purinérgico P2 , Mucosa Respiratória/metabolismo , Trifosfato de Adenosina/agonistas , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/imunologia , Trifosfato de Adenosina/metabolismo , Amidas/farmacologia , Animais , Brônquios/imunologia , Brônquios/patologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Broncoconstritores/agonistas , Broncoconstritores/farmacologia , Cálcio/imunologia , Cálcio/metabolismo , Sinalização do Cálcio/imunologia , Células Cultivadas , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Cobaias , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/imunologia , Masculino , Cloreto de Metacolina/agonistas , Cloreto de Metacolina/farmacologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Técnicas de Cultura de Órgãos , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/imunologia , Fosfoproteínas Fosfatases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Piridinas/farmacologia , Receptores Purinérgicos P2/imunologia , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Fatores de Tempo , Quinases Associadas a rho , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/imunologia , Quinases da Família src/metabolismoRESUMO
BACKGROUND: It is well known that beta-adrenoceptor agonists (beta-agonists) cause relaxation in airway smooth muscle mediated by a reduction in the concentration of intracellular Ca2+ ([Ca2+](i)). However, little is currently known regarding whether reduced sensitization to Ca2+ is involved in the beta-adrenergic relaxation. OBJECTIVE: This study was designed to determine the intracellular mechanisms underlying suppression of Ca2+ sensitization in beta-adrenergic relaxation (Ca(2+)-independent relaxation by beta-agonists). Methods Isometric tension and [Ca2+](i) were simultaneously measured in fura-2-loaded strips isolated from guinea-pig tracheal smooth muscles. The relationships between tension and [Ca2+](i) were examined in the inhibitory action of isoprenaline (ISO) and other cAMP-related agents against methacholine-induced contraction. RESULTS: The concentration-inhibition curve for ISO against methacholine in tension was significantly dissociated from the curve for ISO in [Ca2+](i). In ISO-induced relaxation, a reduction in tension was significantly greater than that in [Ca2+](i.) This phenomenon was mimicked by other cAMP-related agents: forskolin and dibutyryl-cAMP. In contrast, the inhibitory action of SKF-96365, a non-selective inhibitor of Ca(2+) channels, was associated with that in [Ca2+](i). In the presence of Rp-cAMPS, an inhibitor of protein kinase A (PKA), ISO caused an equivalent relaxation with less reduction in [Ca2+](i). The effects of ISO were not affected by Y-27632, an inhibitor of Rho-kinase, or by bisindolylmaleimide, an inhibitor of protein kinase C. ISO failed to inhibit contraction elicited by calyculin A, an inhibitor of myosin phosphatase. Conclusion beta-Adrenergic action antagonizes not only Ca2+ mobilization but also Ca2+ sensitization in methacholine-induced contraction. The cAMP/PKA-independent, G(s)-direct action is more potent in Ca(2+)-independent relaxation by beta-agonists than the cAMP/PKA-dependent pathway. Moreover, myosin phosphatase is a fundamentally affected protein in the reduced response to Ca2+ mediated by beta-agonist. Our results may provide evidence that this Ca2+ desensitization is a novel target for a reliever medication using rapid-acting beta-agonists in acute asthma management.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Cálcio/metabolismo , Isoproterenol/farmacologia , Músculo Liso/efeitos dos fármacos , Amidas/farmacologia , Animais , Asma/tratamento farmacológico , Bucladesina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Colforsina/farmacologia , Proteína Receptora de AMP Cíclico/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Depressão Química , Fura-2 , Cobaias , Imidazóis/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Maleimidas/farmacologia , Toxinas Marinhas , Cloreto de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/antagonistas & inibidores , Oxazóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Traqueia , Quinases Associadas a rhoRESUMO
BACKGROUND: TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts. The purpose of this phase I study was to evaluate the safety and toxicity, maximum tolerated dose, pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity of TZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients with refractory solid tumors. PATIENTS AND METHODS: Patients had a histologically verified refractory tumor with measurable disease, were > or = 18 years old, had an Eastern Cooperative Oncology Group performance status <2 and adequate bone marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as platelets <25 x 10(9)/l, neutrophils <0.5 x 10(9)/l for >5 days, febrile neutropenia > or = 38.5 degrees C with grade 4 (National Cancer Institute-common toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding nausea and vomiting. The last dose was the dose where > or = 2 out of six patients experienced dose-limiting toxicity in cycle one. The maximum tolerated dose was one dose level below with less than two of six patients with dose-limiting events. RESULTS: Twenty-one non-selected, fully evaluable patients were enrolled. The majority were male (19) and the median age was 55 years (range 39-67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m(2). The median number of cycles was two (range 1-4). Dose-limiting toxicities were observed in three patients at the 3.0 mg/m(2) dose level, including neutropenia, fatigue and a short lasting, reversible peripheral neurotoxic syndrome. The most common toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation, leukopenia and neutropenia. Based on RECIST criteria, the best response was stable disease in seven patients. The pharmacokinetic evaluation revealed a T(1/2) of approximately 7 h and linear kinetics. CONCLUSIONS: The recommended dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m(2). Neutropenia, fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with this schedule. TZT-1027 may be associated with neurological side-effects in patients previously exposed to neurotoxic compounds such as oxaliplatin.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacocinética , Adulto , Idoso , Alopecia/induzido quimicamente , Anorexia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Área Sob a Curva , Constipação Intestinal/induzido quimicamente , Depsipeptídeos , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Feminino , Humanos , Infusões Intravenosas , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Oligopeptídeos/efeitos adversos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/uso terapêuticoRESUMO
PURPOSE: To predict the optimal dosage for nedaplatin ( cis-diammineglycolatoplatinum), an anticancer drug and a platinum derivative like cisplatin and carboplatin, a simple formula was developed based on renal function in Japanese adult cancer patients. PATIENTS AND METHODS: Unbound platinum concentrations in plasma after intravenous infusion of nedaplatin were measured for 187 courses in 145 patients with lung, esophageal, and cervical and ovarian cancer undergoing clinical treatment. The data were divided into two sets, a model development data set of 94 courses and a validation data set of 93 courses. Regression analysis was applied to the relationship between the unbound platinum clearance (CL) of nedaplatin and the patients' renal function. The predictability and usefulness of this formula were assessed by validation using the external data set of 93 courses obtained from 75 patients. RESULTS: A simple formula was obtained for predicting the platinum clearance using the creatinine clearance (CLcr): CL=0.0836xCLcr+3.45. Indices for the predictive performance for CL and the area under the plasma concentration curve (AUC) in the validation data were almost the same as those for the model development data. CONCLUSIONS: A formula for predicting the CL of unbound platinum after nedaplatin administration was developed, and only CLcr was found to be a significant covariate of the CL. This formula was useful for estimating the CL for the second as well as the first treatment with nedaplatin.
Assuntos
Antineoplásicos/administração & dosagem , Rim/fisiologia , Modelos Teóricos , Compostos Organoplatínicos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacocinética , Análise de RegressãoAssuntos
Células Dendríticas Foliculares/patologia , Omento/patologia , Neoplasias Peritoneais/patologia , Sarcoma/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Evolução Fatal , Humanos , Masculino , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/radioterapia , Neoplasias Peritoneais/cirurgia , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Sarcoma/cirurgiaRESUMO
The aim of the present study was to investigate the effects of short-term physical exercise that did not change body mass on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in 39 non-obese Japanese type 2 diabetic patients. Insulin sensitivity and insulin secretion were estimated with homeostasis model assessment insulin resistance (HOMA-IR) and HOMA-B-cell function proposed by Matthews et al., respectively. All patients were hospitalized and were engaged in low-intensity exercise that consisted of walking and dumbbell exercise for successive 7 days. There were no changes in hospital diet and the dose of any medications used throughout the study. Fasting glucose, insulin, and lipids were measured before and after exercise. After exercise, serum triglyceride levels significantly decreased, but no significant changes were observed in total and HDL cholesterol concentrations. Fasting glucose, insulin, and HOMA-IR levels significantly decreased after exercise, but HOMA-B-cell function did not change during the study. There was no significant difference between BMI levels before and after exercise. From these results, it can be concluded that short-term (7 days) low-intensity physical exercise combined with hospital diet reduces serum triglycerides, insulin resistance, and fasting glucose levels without affecting BMI in non-obese Japanese type 2 diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico/fisiologia , Glucose/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Metabolismo dos Lipídeos , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Homeostase/fisiologia , Humanos , Insulina/sangue , Insulina/fisiologia , Secreção de Insulina , Japão , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
PURPOSE: A Phase I study of exatecan, a new water-soluble camptothecin derivative, was conducted to determine the maximum tolerated dose and a recommended dose, according to an internationally standardized core protocol. Pharmacological profiles of lactone and total (lactone + carboxylate) exatecan were also investigated. PATIENTS AND METHODS: Fifteen patients with advanced solid malignancies were treated with 3, 5, and 6.65 mg/m(2) of exatecan infused over 30 min every 3 weeks. Concentrations of lactone, total drug, and a metabolite in plasma and urine were determined during the first course. RESULTS: Dose-limiting neutropenia and liver dysfunction were observed in two of six patients at 6.65 mg/m(2), but no grade 3 or worse diarrhea was observed. Emesis was moderate, and no grade 3 or worse nausea and vomiting were observed at a recommended dose of 5 mg/m(2), with prophylactic use of granisetron. Pharmacokinetics were linear and had moderate variability; clearances of lactone and total drug were 6.8 +/- 2.8 and 2.1 +/- 1.1 (mean +/- SD) l/h/m(2), respectively. The ratio of lactone concentration to total drug concentration in plasma decreased from 0.81 +/- 0.06 at the end of infusion to 0.15 +/- 0.06 10 h after the infusion. The lactone:total ratio of drug exposure was 0.30 +/- 0.08, ranging from 0.16 to 0.43. Neutropenia was related to the drug exposure of both lactone and total drug. CONCLUSIONS: The recommended dose of exatecan infused over 30 min every 3 weeks is 5 mg/m(2), with a favorable toxicity profile of mild and infrequent diarrhea. Interpatient variability of pharmacokinetics was similar to or smaller than that with other camptothecin derivatives.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
We established a highly sensitive quantitative analytical method for chondroitin/dermatan sulfates by LC/MS method. By this method, the unsaturated disaccharides produced after the enzymatic digestion of chondroitin/dermatan sulfates can be determined in the amounts as low as 0.5 pmol levels. The use of tetrabutylammonium hydroxide as an ion-pair reagent for LC/MS allowed us to separate unsaturated 4-sulfated disaccharide and unsaturated 6-sulfated disaccharide. Furthermore, the peak areas of unsaturated disaccharides were increased almost 10 times by the postcolumn addition of acetonitrile. We applied this LC/MS method to the analyses of unsaturated disaccharides from chondroitin/dermatan sulfates in the tissues sections on glass slides, which were prepared from MethA tumor-bearing mice. This method brought about considerable reduction in the time distance from sample collection to preparation of analytical results.