RESUMEN
BACKGROUND: The results of the EMPA-REG-OUTCOME trial on type 2 diabetic patients at high risk for prior cardiovascular events showed that empagliflozin produces a remarkable reduction in the rates of hospitalization for heart failure (35%), cardiovascular death (38%), and all-cause death (32%). This unexpected cardio-protective action cannot be accounted for by the improvement of "classical" cardiovascular risk factors. AIMS: This review aims at summarizing current knowledge on the cardiovascular action of SGLT2 inhibitors and discuss the different hypotheses formulated to explain the results of the EMPA-REG-OUTCOME-study. DATA SYNTHESIS: We discuss in detail the major cardiovascular outcomes of the study in the light of the potential systemic and myocardial mechanisms of action of the drug. In addition, we propose and speculate on a direct effect of empagliflozin on cardiomyocytes. CONCLUSIONS: The available evidence is insufficient to establish any of the proposed mechanisms of cardiovascular action of empagliflozin. While awaiting for the results of ongoing clinical studies with other SGLT2 inhibitors, the most promising putative mechanisms still deserve to be confirmed with specifically designed, yet unavailable, pre-clinical studies.
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Compuestos de Bencidrilo/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Corazón/fisiopatología , Hipoglucemiantes/uso terapéutico , Riñón/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Compuestos de Bencidrilo/efectos adversos , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/fisiopatología , Glucósidos/efectos adversos , Humanos , Hipoglucemiantes/efectos adversos , Riñón/metabolismo , Riñón/fisiopatología , Miocitos Cardíacos/metabolismo , Medición de Riesgo , Factores de Riesgo , Transportador 2 de Sodio-Glucosa/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Bone modulates testis function through osteocalcin (OCN) production. This paper assesses the association between serum OCN and androgen production recovery in morbidly obese males at 9 months after bariatric surgery. SUBJECTS: A cohort of n=103 obese males with mean±s.d. body mass index (BMI) 47.7±8.2 kg m(-2), age 42±11 years, consisting of n=76 patients undergoing gastric bypass and n=27 in the waiting list for surgery. RESULTS: At 9 months from surgery, a significant increase was observed in mean±s.d. total OCN (tOCN=10.4±10.3 ng ml(-1), P<0.001) and undercarboxylated OCN (ucOCN=5.4±3.7 ng ml(-1), P<0.001), total testosterone (TT, 5.6±6.5 nM, P<0.001) and calculated free testosterone (cFT, 0.035±0.133 nM, P<0.006), sex hormone binding globulin (SHBG, 21.2±16.7 nM, P<0.001) and decrease in estradiol (E2, -30.1±51.9 pM, P<0.001) levels only in operated patients, with a significant reduction in BMI (24%) and waist (20%). A positive correlation existed between tOCN and ucOCN (age-adjustment (age-adj.): ß=0.692, P<0.001) and their variations (age-adj.: ß=0.629, P<0.001) after surgery. Multivariate analysis in operated patients showed a significant positive association between variations in tOCN and TT (age-adj.: ß=0.289, P=0.012), SHBG (age-adj.: ß=0.326, P=0.005) but not with cFT variation. tOCN, but not luteinizing hormone (LH) variation was the only significant predictive factor of cFT recovery in the hypogonadal (TT<12 nM) operated subjects even after age- and BMI-adjustment (adj.: ß=0.582, P<0.05). cFT improvement was significantly higher when considering operated patients with tOCN increase (0.045±0.123 vs -0.02±0.118 nM, P=0.015), hypogonadism (0.059±0.111 vs -0.059±0.138 nM, P=0.002) and younger than 35 years (0.102±0.108 vs -0.019±0.123 nM, P=0.009). CONCLUSION: OCN recovery observed after bariatric surgery is significantly associated with cFT improvement independently of BMI variation and age in hypogonadal morbidly obese males.
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Andrógenos/metabolismo , Derivación Gástrica , Hipogonadismo/cirugía , Obesidad Mórbida/cirugía , Osteocalcina/metabolismo , Testosterona/metabolismo , Adulto , Índice de Masa Corporal , Hormona Folículo Estimulante/metabolismo , Humanos , Hipogonadismo/etiología , Hipogonadismo/metabolismo , Estudios Longitudinales , Hormona Luteinizante/metabolismo , Masculino , Obesidad Mórbida/complicaciones , Obesidad Mórbida/metabolismo , Valor Predictivo de las Pruebas , Estudios Prospectivos , Inducción de Remisión , Globulina de Unión a Hormona Sexual/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Sputum eosinophil counts and eosinophil cationic protein (ECP) levels are usually increased in asthmatic patients. The correlation between sputum eosinophils or ECP and clinical findings of asthma has been previously investigated but many of these studies have been performed on small samples of asthmatic patients, considering only few clinical indices and often including patients on oral or inhaled corticosteroids, which might be confounding when interpreting the relationship between disease activity and airway inflammation. OBJECTIVE: To assess whether sputum eosinophils and ECP were differently related to functional and clinical parameters of asthma in a large number of steroid-naïve asthmatic patients, taking into account several potential determinants of activity and chronicity of asthma. METHODS: One hundred and twenty-nine patients with mild-moderate asthma were studied. Sputum was induced by hypertonic saline inhalation and processed using the whole sample method. RESULTS: Sputum eosinophils and ECP significantly correlated with each other (r = 0.41, P < 0.001). When patients were grouped on the basis of high/low sputum eosinophils and high/low sputum ECP levels, significant differences were observed among groups, with patients with high sputum eosinophils and ECP showing the greatest asthma severity. In the overall sample, disease duration inversely correlated with sputum eosinophils, whereas FEV1 and peak expiratory flow (PEF) inversely correlated with sputum ECP. Rescue ß2 -agonist use and total symptom score positively correlated with both eosinophil counts and sputum ECP. Stepwise regression analysis showed that symptom score and disease duration accounted for 17.6% of sputum eosinophil variance, whereas symptom score and FEV1 accounted for 14.7% of sputum ECP variance. CONCLUSIONS AND CLINICAL RELEVANCE: Both sputum eosinophils and ECP are weakly related to clinical markers of asthma severity. However, ECP was more closely related to lung function parameters than eosinophil counts.
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Asma/inmunología , Asma/metabolismo , Proteína Catiónica del Eosinófilo/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Adulto , Asma/diagnóstico , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Estudios Retrospectivos , Factores de Riesgo , Esputo/citología , Esputo/inmunología , Adulto JovenRESUMEN
Here we provide evidence, along an 8-year period time-series based on multifaceted data from a Mediterranean marine protected area (MPA), whether protection can tackle invasive and range expanding herbivore fishes, and their effects on the algal resource availability, taking into account the population trends of predatory fishes, fisheries catches of herbivore fishes and sea surface temperature (SST) through time. Our findings pointed out that an ineffective in restoring top-down control process MPA may facilitate, rather than alleviate, the sudden and enduring population burst of invasive and range-expanding herbivorous fishes at tipping points of abrupt change. This subsequently results in the deterioration of rocky reef habitats and the depletion of algal resources, with the tipping points of abrupt change for algal and herbivore fish species not overlapping chronologically. As sea temperature increases, ineffective or recently established MPAs may inadvertently facilitate the proliferation of invasive and range-expanding species, posing a significant challenge to management effectiveness and conservation objectives.
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Ecosistema , Herbivoria , Animales , Peces , Explotaciones Pesqueras , Temperatura , Conservación de los Recursos NaturalesRESUMEN
BACKGROUND: Long-term follow-up of diisocyanate-induced occupational asthma has been occasionally reported. METHODS: We studied the outcome of toluene diisocyanate (TDI)-induced asthma in 46 patients at diagnosis and after a follow-up of 11 ± 3.6 years. Symptoms, anti-asthma therapy, forced expiratory volume in 1 s (FEV1) and bronchial hyperresponsiveness to methacholine were assessed. RESULTS: A significant improvement in FEV1 (% predicted) and PD20FEV1 methacholine was observed at follow-up in comparison with diagnosis. Anti-asthma treatment was performed by 42% of patients at diagnosis and by 70% at follow-up. At the time of follow-up, 32 subjects had been removed from exposure for 6.0 ± 6.9 years, whereas 14 subjects continued to work with reduced exposure to TDI. There was a significant reduction in the prevalence of attacks of shortness of breath and dyspnoea at follow-up, but only in unexposed patients. PD20FEV1 was significantly improved only in patients with a lower FEV1 at diagnosis and in those who have ceased work. Logistic regression analysis, using different models with some independent variables, showed that there were no significant determinants of improvement in FEV1 at follow-up, while a shorter duration of symptoms before diagnosis was a significant predictor of improvement in PD20FEV1 at follow-up. CONCLUSIONS: Asthma-like symptoms, bronchial hyperresponsiveness and airway obstruction improved, but did not normalize, after a long-term follow-up with cessation or reduction in TDI exposure, mainly in subjects with an early diagnosis of occupational asthma and in patients with a lower baseline FEV1 no longer exposed to TDI.
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Asma Ocupacional/inducido químicamente , Exposición Profesional/efectos adversos , 2,4-Diisocianato de Tolueno/envenenamiento , Adulto , Antiasmáticos/uso terapéutico , Asma Ocupacional/tratamiento farmacológico , Asma Ocupacional/inmunología , Pruebas de Provocación Bronquial/métodos , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , 2,4-Diisocianato de Tolueno/inmunologíaRESUMEN
AIMS: Several studies have investigated the effects of metformin treatment in patients with type 1 diabetes mellitus (T1DM). No study has hitherto examined its effects on endothelial function in these patients. In this study we sought to evaluate the effect of metformin on endothelial function in type 1 diabetic patients. METHODS: Forty-two uncomplicated T1DM patients were randomized in a placebo-controlled, double-blind, 6-month trial to treatment with either metformin or placebo. Glycometabolic and clinical parameters as well as flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the right brachial artery were measured at baseline and at the end of the study. Glycaemic variability (GV, calculated from continuous glucose monitoring data) and a biomarker of oxidative stress [urinary 8-iso-prostaglandin F2α (PGF2α)] were also assessed. RESULTS: Baseline data were similar in the two groups. Compared with placebo, metformin significantly reduced body weight [-2.27 kg (95% confidence interval: -3.99; -0.54); p = 0.012] whilst improved FMD [1.32% (0.30; 2.43); p = 0.013] and increased PGF2α [149 pg/mg creatinine (50; 248); p = 0.004]. Notably, the improvement of FMD did not correlate with the decrease of body weight (r(2) < 1%). NMD, haemoglobin A1c, GV, daily insulin dose and other parameters did not significantly change after the treatment comparing the two groups. CONCLUSIONS: Our pilot trial showed that, in uncomplicated type 1 diabetic subjects, metformin improved FMD and increased PGF2α, a marker of oxidative stress, irrespective of its effects on glycaemic control and body weight. Randomized, blinded clinical trials are needed to evaluate the benefits and risks of metformin added to insulin in type 1 diabetes.
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Arteria Braquial/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Metformina/uso terapéutico , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Glucemia/metabolismo , Arteria Braquial/fisiopatología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Dinoprost/metabolismo , Método Doble Ciego , Quimioterapia Combinada , Endotelio Vascular/fisiopatología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Estrés Oxidativo/efectos de los fármacos , Proyectos Piloto , Resultado del Tratamiento , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Few data are reported on the effects of a reduction of exposure to specific sensitizers in occupational asthma (OA). The objective of this study was to evaluate the clinical outcome of subjects with OA, comparing the effect of a reduction with that of the persistence or cessation of occupational exposure to the specific sensitizer. SUBJECTS AND METHODS: Forty-one subjects with OA due to different sensitizers were diagnosed via a specific inhalation challenge. After a follow-up interval of 3.5 years, subjects were reexamined by clinical assessment, bronchial hyperresponsiveness (BH) and induced sputum. RESULTS: At follow-up, subjects who had reduced occupational exposure (n = 22) showed a significant improvement in BH and a nonsignificant improvement in sputum eosinophilia (from 5.3 to 1.1%, n.s.), while subjects still exposed (n = 10) showed a significant decrease in FEV(1). Subjects who ceased work (n = 9) showed a trend of improvement in BH and sputum eosinophilia. Logistic analysis showed that the major determinant of improvement in BH at follow-up was the severity of BH at diagnosis, with a minimal contribution from the duration of exposure and treatment with inhaled corticosteroids during follow-up; reduction of work exposure did not enter into any model. CONCLUSION: The reduction of occupational exposure could not be considered to be as effective as work cessation, which remained the best treatment for OA. However, it was not associated with a deterioration of FEV(1) as observed in subjects with persistent exposure.
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Asma Ocupacional/prevención & control , Exposición Profesional , Ausencia por Enfermedad , Adulto , Asma Ocupacional/diagnóstico , Pruebas de Provocación Bronquial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
The purpose of this study was to describe epidemiological, clinical and microbiological characteristics of confirmed novel influenza A (H1N1) infection, investigating factors associated with disease severity. We retrospectively selected patients seeking care for respiratory symptoms in two periods (May-August and September-November 2009) with different epidemiological characteristics. Only patients with confirmed pandemic influenza A (H1N1) were enrolled in this study. A total of 104 patients with H1N1 infection were evaluated, mostly referring classic influenza symptoms; in addition, diarrhea and vomiting were often referred. Clinical signs, symptoms and respiratory complications were different in the two periods. Of all patients, 18 (17%) had pneumonia. Patients older than 50 years showed a lower probability of pneumonia diagnosis when compared to children aged 0-13 (p = 0.049); a longer duration of symptoms before medical care was associated with a higher probability of pneumonia (p = 0.026). Phylogenetic analysis showed a low variability both in hemagglutinin and neuraminidase genes. In addition, no neuraminidase mutation associated with antiviral resistance was detected. A detailed description of respiratory diseases associated with H1N1 infection was provided and factors associated with its severity were investigated, thus contributing to the insight into epidemiological, clinical and microbiological knowledge of the disease.
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Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/epidemiología , Gripe Humana/fisiopatología , Pandemias , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Antivirales , Niño , Diarrea/virología , Brotes de Enfermedades , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Subtipo H1N1 del Virus de la Influenza A/clasificación , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/virología , Italia/epidemiología , Masculino , Filogenia , Neumonía Viral/virología , Vómitos/virología , Adulto JovenRESUMEN
BACKGROUND: Oxidative stress plays a role in the pathogenesis of many chronic inflammatory lung diseases. Exhaled breath condensate (EBC) collection is a noninvasive method to investigate pulmonary oxidative stress biomarkers such as malondialdehyde (MDA). SUBJECTS AND METHODS: We measured MDA levels in EBC in a large number of patients (N = 194) with respiratory diseases: asthma (N = 64), bronchiectasis (BE, N = 19), chronic obstructive pulmonary disease (COPD, N = 73), idiopathic pulmonary fibrosis (IPF, N = 38). Fourteen healthy nonsmoking subjects were included as controls. RESULTS: Excluding IPF subjects, MDA levels were significantly higher in all disease groups than in control group. MDA was significantly higher in COPD than asthmatic and BE subjects. Among asthmatics, corticosteroids-treated subjects had lower MDA levels than untreated subjects. COPD subjects showed an inverse correlation between MDA concentrations and FEV(1)% (rho: -0.24, P < .05). CONCLUSIONS: EBC-MDA is increased in subjects with chronic airway disorders, particularly in COPD, and it is related to FEV(1) reduction.
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Biomarcadores/análisis , Espiración , Enfermedades Pulmonares/fisiopatología , Malondialdehído/análisis , Estrés Oxidativo/fisiología , Adulto , Anciano , Pruebas Respiratorias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esputo/químicaRESUMEN
Marine noise pollution (MNP) can cause a multitude of impacts on many organisms, but information is often scattered and general outcomes difficult to assess. We have reviewed the literature on MNP impacts on Mediterranean fish and invertebrates. Both chronic and acute MNP produced by various human activities - e.g. maritime traffic, pile driving, air guns - were found to cause detectable effects on intra-specific communication, vital processes, physiology, behavioral patterns, health status and survival. These effects on individuals can extend to inducing population- and ecosystem-wide alterations, especially when MNP impacts functionally important species, such as keystone predators and habitat forming species. Curbing the threats of MNP in the Mediterranean Sea is a challenging task, but a variety of measures could be adopted to mitigate MNP impacts. Successful measures will require more accurate information on impacts and that effective management of MNP really becomes a priority in the policy makers' agenda.
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Ecosistema , Ruido , Animales , Peces , Humanos , Invertebrados , Mar MediterráneoRESUMEN
Assessing larval dispersal is essential to understand the structure and dynamics of marine populations. However, knowledge about early-life dispersal is sparse, and so is our understanding of the spawning process, perhaps the most obscure component of biphasic life cycles. Indeed, poorly known species-specific spawning modality and species-specific early-life traits, as well as the high spatio-temporal variability of the oceanic circulation experienced during larval drift, hamper our ability to appraise the realized connectivity of coastal fishes. Here, we propose an analytical framework which combines Lagrangian modelling, network theory, otolith analyses and biogeographical information to pinpoint and characterize larval sources which are then grouped into discrete spawning areas. Such well-delineated larval sources allow improving the quantitative evaluations of both dispersal scales and connectivity patterns. To illustrate its added value, our approach is applied to two case-studies focusing on Diplodus sargus and Diplodus vulgaris in the Adriatic sea. We evidence robust correlations between otolith geochemistry and modelled spawning areas to assess their relative importance for the larval replenishment of the Apulian coast. Our results show that, contrary to D. sargus, D. vulgaris larvae originate from both eastern and western Adriatic shorelines. Our findings also suggest that dispersal distances and dispersal surfaces scale differently with the pelagic larval duration. Furthermore, 30.8% of D. sargus larvae and 23.6% of D. vulgaris larvae of the Apulian populations originate from Marine protected area (MPA), exemplifying larval export from MPAs to surrounding unprotected areas. This flexible multidisciplinary framework, which can be adjusted to any coastal fish and oceanic system, exploits the explanatory power of a dispersal model, fine-tuned and backed-up by observations, to provide more reliable scientific basis for the management and conservation of marine ecosystems.
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Ecosistema , Peces , Animales , Conservación de los Recursos Naturales , Larva , Océanos y Mares , Dinámica PoblacionalRESUMEN
OBJECTIVE: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients. PATIENTS AND METHODS: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug. RESULTS: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline. CONCLUSIONS: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.
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Estenosis Coronaria/terapia , Vasos Coronarios/efectos de los fármacos , Dinitrato de Isosorbide/análogos & derivados , Microvasos/efectos de los fármacos , Intervención Coronaria Percutánea , Ranolazina/uso terapéutico , Vasodilatadores/uso terapéutico , Anciano , Circulación Coronaria/efectos de los fármacos , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Estudios Cruzados , Femenino , Humanos , Dinitrato de Isosorbide/efectos adversos , Dinitrato de Isosorbide/uso terapéutico , Masculino , Microcirculación/efectos de los fármacos , Microvasos/diagnóstico por imagen , Microvasos/fisiopatología , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Ranolazina/efectos adversos , Ciudad de Roma , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento , Vasodilatadores/efectos adversosRESUMEN
BACKGROUND: Hypertonic saline (HS) has been shown to modulate in vitro cell functions according to the state of cell activation; however, few studies have evaluated the effect of HS in vivo. Chronic airway inflammation, a major feature of chronic obstructive pulmonary disease (COPD), is associated with an activation of inflammatory and resident cells, which in turn makes them more prompt to respond to further stimuli. OBJECTIVE: To evaluate whether HS might modulate, also in vivo, the release of preformed mediators and intracellular chemokines from airway cells of COPD patients. METHODS: Sputum was induced by inhalation of either HS (4.5% w/v) or isotonic saline (IS 0.9% w/v) solution and processed by plug selection. We measured eosinophil cationic protein (ECP), neutrophil elastase (NE), IL-8 and monocyte chemoattractant protein-1 (MCP-1) in sputum samples obtained by either HS or IS inhalation in 24 COPD patients. RESULTS: No significant difference in mediators measured in sputum samples obtained by the two different inductions was observed; also, there was no significant difference in sputum sample volumes, cell viability, total and differential cell counts. Repeatability between the two tests was high for ECP, NE, macrophages, neutrophils and eosinophils, and satisfactory for IL-8 and MCP-1. CONCLUSIONS: Hyperosmolarity does not affect the levels of the inflammatory mediators and chemokines examined or the cell counts measured in induced sputum obtained from COPD patients. This study does not support the hypothesis that HS can stimulate chemokine and mediator release from airway cells of COPD patients. Therefore, HS and IS can be interchangeably used to measure inflammatory mediators in the sputum supernatant of COPD patients.
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Quimiocinas/metabolismo , Soluciones Isotónicas/farmacología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Solución Salina Hipertónica/farmacología , Esputo/efectos de los fármacos , Esputo/metabolismo , Anciano , Quimiocinas/biosíntesis , Femenino , Humanos , Inhalación , Soluciones Isotónicas/administración & dosificación , Masculino , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Solución Salina Hipertónica/administración & dosificación , SolubilidadRESUMEN
AIM: To find some simple clinical factors which can predict the quality of the sputum samples obtained in a large group of asthmatic subjects. METHODS: We compared the presence of sputum productive cough in the days preceding the test, easiness in expectoration during the test, and sputum macroscopic aspect (presence of visible plugs) with the quality of slides obtained from sputum processing. We also monitored changes in the quality in patients who repeated sputum collection several times, comparing those whose first sample was adequate with those whose first sample was inadequate. We analysed 547 sputum samples obtained from 238 asthmatic patients. Sputum was processed using the whole sample method. RESULTS: Patients with productive cough in the days preceding the test and easy expectoration during the test produced a higher percentage of adequate samples than those without productive cough (86% vs 76 %, p=0.01) and with difficulty in expectoration (85% vs 63%, p=0.0001). "Good" macroscopic samples were associated with better quality of slides (91% vs 38%, p=0.0001). Patients with inadequate first sample (n=40) had a higher percentage of inadequate samples (55%) in the subsequent tests than patients (n=115) with adequate first sample (8%). CONCLUSIONS: Patients with increased airway secretions in the days preceding the test, easy expectoration and "good" macroscopic aspect of the sputum are more likely to produce sputum sample adequate for inflammatory cell analysis. If the first sputum sample is adequate, subsequent samples are very likely to be adequate as well. If the first sputum sample is inadequate, the quality of subsequent samples cannot be predicted, since there are similar probabilities of having adequate or inadequate samples.
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Asma/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Esputo/citología , Adulto , Asma/complicaciones , Tos/etiología , Tos/patología , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
In order to identify predictors of recurrence of asthma symptoms after withdrawal of therapy in mild persistent asthmatics, asymptomatic on low-dose inhaled corticosteroids (ICS), we studied 87 asthmatic patients regularly treated with ICS for at least 6 months. At the enrollment visit (T1), 71 on ICS were asymptomatic over the past 3 months and discontinued asthma treatment. Symptoms and PEF were then monitored for up to 3 months or until symptoms recurred (T2). At T1 and T2, all subjects underwent methacholine challenge and sputum induction. Thirty nine out of 71 patients experienced symptom recurrence. At T1, clinical and functional data and sputum eosinophilia between patients with or without recurrence of symptoms were similar. Age > 40 yr, and disease duration > 5 yr were significantly associated with recurrence of asthma symptoms, while the presence of allergic rhinitis, low baseline FEV(1) and untreated time span > 60 months showed a trend to be associated with symptoms recurrence. At T2, symptoms, pulmonary function, bronchial hyperresponsiveness and sputum eosinophilia deteriorated in patients with symptom recurrence but not in patients without symptom recurrence. In conclusion, age and asthma duration were the best predictors of symptom recurrence in mild persistent asthmatics who withdrew pharmacological therapy, as recommended in the step-down of international guidelines.
Asunto(s)
Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/inmunología , Esputo/inmunología , Administración por Inhalación , Adolescente , Adulto , Factores de Edad , Anciano , Asma/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ápice del Flujo Espiratorio , Valor Predictivo de las Pruebas , Recurrencia , Factores de TiempoRESUMEN
STUDY OBJECTIVE: To determine the protective effect of salbutamol, 100 microg, inhaled by different devices (pressurized metered-dose inhaler [pMDI; Ventolin; GlaxoWellcome; Greenford, UK], pMDI + spacer [Volumatic; GlaxoWellcome], or breath-activated pMDI [Autohaler; 3M Pharmaceuticals; St. Paul, MN]) on bronchoconstriction induced by methacholine. DESIGN: Randomized, double-blind, cross-over, placebo-controlled study. PATIENTS: Eighteen subjects with stable, moderate asthma, asymptomatic, receiving regular treatment with salmeterol, 50 microg bid, and inhaled beclomethasone dipropionate, 250 microg bid, in the last 6 months, with high hyperreactivity to methacholine (baseline provocative dose of methacholine causing a 20% fall in FEV(1) [PD(20)] geometric mean [GM], 0.071 mg). Subjects were classified into two groups: subjects with incorrect (n = 5) pMDI inhalation technique, and subjects with correct (n = 13) inhalation technique. METHODS AND MEASUREMENTS: After cessation of therapy for 3 days, all subjects underwent four methacholine challenge tests, each test 1 week apart, each time 15 min after inhalation of salbutamol, 100 microg (via pMDI, pMDI + spacer, or Autohaler), or placebo. The protective effect on methacholine challenge test was evaluated as the change in the PD(20), and expressed in terms of doubling doses of methacholine in comparison with placebo treatment. RESULTS: The PD(20) was significantly higher after salbutamol inhalation than after placebo inhalation, but no significant difference was observed among the three different inhalation techniques. Only when salbutamol was inhaled via pMDI + spacer, PD(20) was slightly but not significantly higher (pMDI GM, 0.454 mg; pMDI + spacer GM, 0.559 mg; and Autohaler GM, 0.372 mg; not significant [NS]) than other inhalation techniques. Similar results (mean +/-SEM) were obtained with doubling doses of methacholine (pMDI, 2 +/- 0.47; pMDI + spacer, 3 +/- 0.35; and Autohaler, 2.4 +/- 0.40; NS). No significant difference was found among techniques when subjects with correct or incorrect inhalation technique were separately considered. CONCLUSIONS: Our data show that the protective effect of salbutamol, 100 microg, on methacholine-induced bronchoconstriction is not affected by the different inhalation techniques, although inhalation via pMDI + spacer tends to improve the bronchoprotective ability of salbutamol. These data confirm the clinical efficacy of salbutamol, whatever the device, and the patient's inhalation technique.
Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Albuterol/administración & dosificación , Asma/tratamiento farmacológico , Pruebas de Provocación Bronquial , Broncodilatadores/administración & dosificación , Cloruro de Metacolina , Nebulizadores y Vaporizadores , Adolescente , Adulto , Anciano , Albuterol/efectos adversos , Asma/diagnóstico , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/tratamiento farmacológico , Broncodilatadores/efectos adversos , Estudios Cruzados , Método Doble Ciego , Diseño de Equipo , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
STUDY OBJECTIVE: One week of regular treatment with salmeterol can induce tolerance to the protective effect of a beta2-agonist on early airway response to allergen (EAR). The objective was to assess whether inhaled corticosteroids revert tolerance to salmeterol. STUDY DESIGN: The study had a randomized, double-blind, placebo-controlled design. PATIENTS AND METHODS: Twelve subjects with mild allergic asthma and positive result of specific bronchial provocation test (sBPT) to allergen underwent three sBPTs, separated by 1 week. sBPT was done in all subjects after a single dose (T1) and after 1 week of regular treatment with inhaled salmeterol (50 microg bid) (T2) in order to induce tolerance. Subjects were then randomized to receive either the same dose of salmeterol + beclomethasone dipropionate (BDP, 500 microg bid) (group 1, n = 6) or placebo + BDP (group 2, n = 6) for 1 week before sBPT (T3). RESULTS: After a single dose of salmeterol (T1), all subjects were protected against EAR, whereas after 1 week of regular treatment, the protective effect of salmeterol was totally or partially lost (T2). Maximum FEV1 percent fall (MaxdeltaFEV1%) after allergen inhalation was significantly higher at T2 than at T1. All subjects except one of group 1 were protected against EAR after salmeterol + BDP (T3), and MaxdeltaFEV1% at T3 (median, 12%; range, 4 to 6%) was significantly lower than T2 (median, 22%; range, 12 to 43%; p < 0.05 by Wilcoxon test). Subjects of group 2 did not show any significant protection against EAR after placebo + BDP treatment (T3) MaxdeltaFEV1% at T2 (median, 31%; range, 9 to 40%) and T3 (median, 31%; range, 3 to 42%; not significant). CONCLUSIONS: In conclusion, the addition of inhaled BDP partially restored the bronchoprotective effect of salmeterol on allergen challenge that was lost after 1 week of regular treatment with salmeterol alone. This ability of BDP in reverting tolerance cannot be ascribed to a direct effect of corticosteroids per se on allergen challenge in this group of asthmatics.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Albuterol/análogos & derivados , Asma/tratamiento farmacológico , Beclometasona/farmacología , Broncodilatadores/farmacología , Glucocorticoides/farmacología , Administración por Inhalación , Adolescente , Agonistas Adrenérgicos beta/administración & dosificación , Adulto , Albuterol/administración & dosificación , Albuterol/farmacología , Asma/fisiopatología , Beclometasona/administración & dosificación , Pruebas de Provocación Bronquial , Broncodilatadores/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Tolerancia a Medicamentos , Femenino , Volumen Espiratorio Forzado , Glucocorticoides/administración & dosificación , Humanos , Masculino , Xinafoato de SalmeterolRESUMEN
Long-term change in nonspecific and specific bronchial hyperresponsiveness was studied in 16 subjects with asthma induced by toluene diisocyanate (TDI). A significant positive correlation between months of follow-up and provocative dose inducing a 20 percent fall in FEV1 (PD20FEV1) methacholine was observed in 5 of 16 subjects. In 4 of these 5 subjects, a PD20FEV1 > 1 mg of methacholine was observed 30 to 48 months after the end of TDI exposure. In most subjects, nonspecific bronchial hyperresponsiveness did not change. Nine of 16 subjects became nonresponsive to TDI at follow-up examination, but only 3 of these showed a significant increase in PD20FEV1 methacholine. Seven subjects were still responsive to TDI. Recovery from TDI-induced asthma can occur and only after long-term work cessation. Nonspecific bronchial hyperresponsiveness to methacholine can persist even in the absence of bronchial hyperresponsiveness to TDI, suggesting permanent chronic damage to mechanisms controlling airway tone.
Asunto(s)
Asma/fisiopatología , Hiperreactividad Bronquial , Enfermedades Profesionales/fisiopatología , 2,4-Diisocianato de Tolueno/efectos adversos , Adulto , Asma/inducido químicamente , Pruebas de Provocación Bronquial , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Cloruro de Metacolina , Persona de Mediana Edad , Enfermedades Profesionales/inducido químicamente , Factores de TiempoRESUMEN
STUDY OBJECTIVE: To assess whether the withdrawal of salmeterol treatment for 3 days (72 h) can restore its bronchoprotective ability on specific bronchial provocative test (sBPT) with allergen, which was completely lost after 1 week of regular treatment with salmeterol. STUDY DESIGN: Single-blind design. PATIENTS AND METHODS: We investigated 10 nonsmoking subjects (8 men and 2 women; mean +/- SD age, 24 +/- 8 years) with mild intermittent allergic asthma in the stable phase of the disease, who were never previously treated with regular beta(2)-agonists. Subjects with a previous positive early airway response (EAR) to a screening allergen challenge were considered. They underwent sBPT with allergen after a single dose of inhaled salmeterol, 50 microg (T(1)), and then underwent sBPT after 1 week of regular treatment with inhaled salmeterol, 50 microg bid (T(2)); after that, they continued inhaled salmeterol treatment for 4 days, and then changed to inhaled salmeterol with placebo (two puffs bid) for 3 days (72 h) and underwent sBPT with allergen after a single dose of salmeterol, 50 microg (T(3)). RESULTS: EAR to allergen (DeltaFEV(1) > or = 20% with respect to postdiluent value) was completely abolished by a single dose of salmeterol (T(1); protection index [PI] > or = 50% in all subjects), but it was still present after 1 week of regular treatment with salmeterol (T(2); PI < 50% in all subjects). The maximum FEV(1) percentage fall during sBPT with allergen was significantly lower after withdrawal of regular inhaled salmeterol (T(3)) than after regular treatment with salmeterol (T(2)) (mean, 23% vs 29.5%; range, 4 to 41% vs 18 to 49%, respectively; p < 0.05); a similar result was obtained considering the PI of salmeterol on sBPT with allergen (mean, 44% vs 20%; range, 2 to 86% vs - 11 to 49%, respectively; p < 0.05). However, the maximum FEV(1) percentage fall and PI were significantly different in T(3) than after T(1), and only 4 of 10 patients showed in T(3) a PI > or = 50%. CONCLUSIONS: The bronchoprotective effect of salmeterol on allergen-induced EAR, completely lost after 1 week of regular treatment with salmeterol, may be partially restored by the withdrawal of salmeterol therapy for 3 days (72 h). However, this withdrawal time period is not sufficient to recover the baseline bronchoprotective efficacy of the first dose of salmeterol.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Albuterol/análogos & derivados , Albuterol/farmacología , Asma/tratamiento farmacológico , Pruebas de Provocación Bronquial , Broncodilatadores/farmacología , Tolerancia a Medicamentos , Adolescente , Agonistas Adrenérgicos beta/administración & dosificación , Adulto , Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Femenino , Humanos , Masculino , Xinafoato de Salmeterol , Método Simple Ciego , Factores de TiempoRESUMEN
Long-term treatment with inhaled beta 2-agonists may be associated with a deterioration in asthma control, potentially due to tolerance. Regular use of short-acting beta 2-agonists has been shown to induce tolerance to allergen or adenosine 5'-monophosphate challenge. The aim of the study was to detect the efficacy of a single dose and a short-term treatment with salmeterol, a long-acting beta 2-agonist, to protect against early asthmatic reaction (EAR) to allergen. Eight subjects with mild allergic asthma underwent two treatment periods in which subjects performed an allergen challenge (specific bronchial provocation test) protected by a single dose (50 micrograms) of salmeterol (Salm-1) followed by a second specific bronchial provocation test after regular treatment with salmeterol for 1 week (Salm-2), or a single dose of placebo (Plac-1) and regular treatment (1 week) with placebo (Plac-2). Each subject performed both treatments in a randomized order. Each time allergen challenge was performed 1 h after last drug inhalation and it was stopped when the same provocative dose of allergen of a previous screening allergen challenge was achieved. The maximum decrease in FEV1 and area under curve in the first hour after allergen inhalation were significantly lower in Salm-1 (max delta FEV1 %, median [range]: 4%[0 to 9]) with respect to Salm-2, Plac-1, Plac-2 (24%[13 to 38], 31%[19 to 50], 30%[6 to 44], respectively, p < 0.001); there was no difference among Salm-2, Plac-1 and Plac-2. In Salm-1, all subjects were protected against EAR, whereas in Salm-2 only 2 subjects showed a partial protection. In conclusion the protective effect of a single dose of salmeterol against allergen-induced EAR was lost after regular treatment with salmeterol for 1 week. The clinical relevance of this mechanism remains to be elucidated.