Publications by authors named "Josuel Ora"

58 Publications

The Time Course of Pulmonary Function Tests in COPD Patients with Different Levels of Blood Eosinophils.

Biomed Res Int 2016 16;2016:4547953. Epub 2016 Oct 16.

Department of Systems Medicine, University of Rome Tor Vergata, Chair of Respiratory Medicine, Rome, Italy.

Only very few studies have investigated the influence of eosinophils on the functional progression of COPD. We aimed at retrospectively analyzing the trend of pulmonary function tests over time in patients with COPD according to two baseline blood eosinophil cell count strata (<2% [EOS-] and ≥2% [EOS+]). We used the last 9-year data present in the database of our outpatient clinic and selected only those who had two blood counts that would guarantee the stability of the value of eosinophils and serial spirometry for 4 consecutive years. The analysis of the time course of the spirometric variables analysed showed differences in FEV1 and FVC decline between the subjects of the EOS- group and those of the EOS+ group. The integrated evaluation of our results suggests that the different level of blood eosinophils in the two groups may have influenced independently the time course of the pulmonary function tests and identify two subgroups of subjects with specific disease characteristics: the hyperinflator and the rapid decliner, respectively.
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http://dx.doi.org/10.1155/2016/4547953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086365PMC
February 2017

Dual bronchodilation and exacerbations of COPD.

J Thorac Dis 2016 Sep;8(9):2383-2386

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.21037/jtd.2016.08.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059243PMC
September 2016

Gastroesophageal reflux and COPD exacerbations: Is cholinergic-mediated oesophago-bronchial reflex a possible link?

Respirology 2016 11 16;21(8):1496-1497. Epub 2016 Sep 16.

Department of Systems Medicine, Postgraduate School of Respiratory Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.1111/resp.12896DOI Listing
November 2016

Can an increased cholinergic tone constitute a predictor of positive response to tiotropium in patients with moderate asthma?

J Allergy Clin Immunol Pract 2016 Jul-Aug;4(4):791-3

Postgraduate School of Respiratory Medicine, Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy; Department of Systems Medicine, University of Rome, "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1016/j.jaip.2016.03.025DOI Listing
July 2018

Onset of action of budesonide/formoterol Spiromax(®) compared with budesonide/formoterol Turbuhaler(®) in patients with COPD.

Pulm Pharmacol Ther 2016 08 22;39:48-53. Epub 2016 Jun 22.

University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy.

Budesonide/formoterol (BF) is available in two delivery systems, the dry powder inhaler (DPI) Turbuhaler and a pressurized metered dose inhaler (pMDI) for use in patients with asthma or chronic obstructive pulmonary disease (COPD). Spiromax DPI was recently developed as an alternative to Turbuhaler DPI. In the present study, we examined whether there is a difference in the onset of bronchodilatation between BF 320/9 μg delivered by Spiromax and BF 320/9 μg delivered by Turbuhaler in 16 outpatients with stable moderate-to-severe COPD. Our results confirm the rapid onset of action of formoterol when combined with budesonide in patients with COPD and indicate that the onset of bronchodilation induced by BF Spiromax is faster than that elicited by BF Turbuhaler. Furthermore, they show that BF fixed-dose combination does not induce a decrease in SpO2 or an increase in heart rate in patients with COPD, irrespective of the DPI used to deliver this combination. Given the evidence that both inhalers have an equal safety profile, BF Spiromax offers to prescribers and COPD patients an effective alternative to BF Turbuhaler depending also on their preference, availability and cost.
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http://dx.doi.org/10.1016/j.pupt.2016.06.006DOI Listing
August 2016

Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells.

Respir Res 2016 06 13;17(1):70. Epub 2016 Jun 13.

Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy.

Background: Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.

Methods: The effects of glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach.

Results: Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P < 0.05 vs. additive effect). The maximal effect was reached 140 min post-administration. A significant (P < 0.05) synergistic effect was observed during 9 h post-administration on the cholinergic tone, but not on the histaminergic contractility. Co-administration of glycopyrronium and indacaterol reduced the release of acetylcholine from the epithelium but not from bronchi, and enhanced cAMP levels in bronchi and epithelial cells (P < 0.05 vs. control), an effect that was inhibited by the selective KCa(++) channel blocker iberiotoxin. The role of cAMP-dependent pathway was confirmed by the synergistic effect elicited by the adenylate cyclase activator forskolin on glycopyrronium (P < 0.05 vs. additive effect), but not on indacaterol (P > 0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase.

Conclusions: Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium.
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http://dx.doi.org/10.1186/s12931-016-0386-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906998PMC
June 2016

Dog allergen immunotherapy and allergy to furry animals.

Ann Allergy Asthma Immunol 2016 Jun;116(6):590

Postgraduate School of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1016/j.anai.2016.04.007DOI Listing
June 2016

Olodaterol for the treatment of asthma.

Expert Opin Investig Drugs 2016 Jul 23;25(7):861-6. Epub 2016 May 23.

a Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Introduction: Long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) combinations are still the mainstay of asthma therapy but there is a pressing need to increase adherence to the prescribed treatment achievable in general by reducing the dose frequency. Consequently, there is considerable interest within the pharmaceutical industry in the discovery of once-daily β2-agonists (ultra-LABAs) to be used as a part of a combination therapy for treating asthma.

Areas Covered: The authors review the preclinical and clinical development of olodaterol, a new ultra-LABA characterized by an improved selectivity for β2-adrenoceptors and a rather high intrinsic efficacy profile, in asthma. The clinical results were generated by 4 Phase 2 trials, which have enrolled 731 asthmatic patients.

Expert Opinion: The available results indicate that olodaterol is able to induce an effective 24-h bronchodilation and is safe. However, one cannot formulate a solid conclusion on the best dose and/or dose frequency to be used in asthma because trials were not powered to assess the differences between doses and dose frequencies. Apparently, there is no Phase 3 trial planned or ongoing for olodaterol monotherapy in patients with asthma and also no attempt to combine olodaterol with an ICS, which is surprising.
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http://dx.doi.org/10.1080/13543784.2016.1188078DOI Listing
July 2016

Treatment options for moderate-to-very severe chronic obstructive pulmonary disease.

Expert Opin Pharmacother 2016 21;17(7):977-88. Epub 2016 Mar 21.

b Department of Experimental Medicine , Second University of Naples , Naples , Italy.

Introduction: The appropriate drug management of COPD is still based on the use of bronchodilators, possibly associated with an anti-inflammatory agent. However, there are still fundamental questions that require clarification to optimise their use and major unmet clinical needs that must be addressed.

Areas Covered: The advances obtained with the pharmacological options currently consolidated and the different approaches that are often used in an attempt to respond to unmet therapeutic needs are reviewed Expert opinion: In view of the unsatisfactory status of current treatments for COPD, there is an urgent need for alternative and more effective therapeutic approaches that will help to relieve patient symptoms and affect the natural course of COPD, inhibiting chronic inflammation and reversing the disease process or preventing its progression. However, new pharmacologic options have proved difficult to develop. Therefore, it is mandatory to optimize the use of the treatment options at our disposal. However, there are still fundamental questions regarding their use, including the step-up and step-down pharmacological approach, that require clarification to optimise the use of these drugs. It is likely that phenotyping COPD patients would help in identifying the right treatment for each COPD patient and improve the effectiveness of therapies.
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http://dx.doi.org/10.1517/14656566.2016.1155555DOI Listing
September 2016

Differential pharmacology and clinical utility of long-acting bronchodilators in COPD - focus on olodaterol.

Ther Clin Risk Manag 2015 4;11:1805-11. Epub 2015 Dec 4.

Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy ; Department of Systems Medicine, Respiratory Pharmacology Research Unit, University of Rome Tor Vergata, Rome, Italy.

Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 μg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy.
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http://dx.doi.org/10.2147/TCRM.S73581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675639PMC
December 2015

Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders.

Am J Respir Crit Care Med 2016 Feb;193(3):299-309

1 Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.

Rationale: The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown.

Objectives: To examine whether the relationship between inspiratory neural drive to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions.

Methods: We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements.

Measurements And Main Results: In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt.

Conclusions: Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.
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http://dx.doi.org/10.1164/rccm.201504-0841OCDOI Listing
February 2016

Searching for the synergistic effect between aclidinium and formoterol: From bench to bedside.

Respir Med 2015 Oct 13;109(10):1305-11. Epub 2015 Aug 13.

Second University of Naples, Department of Experimental Medicine, Unit of Pharmacology, Naples, Italy.

Aim of our study was to understand if the interaction between aclidinium and formoterol administered at therapeutic doses leads to a synergistic rather than additive broncholytic effect. We tested the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. The analysis of the interaction between aclidinium and formoterol in vitro was measured by applying the Unified Theory, whereas that in COPD patients was measured by applying the Bliss Independence criterion. Aclidinium and formoterol administered alone completely relaxed human isolated bronchial tissues sub-maximally pre-contracted with ACh in a concentration-dependent manner with similar potency (EC50: aclidinium 4.64 ± 0.78 nM, formoterol 2.71 ± 0.21), whereas the interaction of aclidinium plus formoterol produced moderate to strong synergism. Changes in FEV1 values showed that inhaled aclidinium and formoterol induced a significant and time-dependent bronchodilatory effect during the study time. The inhalation of aclidinium and formoterol in combination significantly anticipated at 5 min post-administration the bronchodilatory effect of FEV1, compared with the effect of drugs administered alone. There was a synergistic interaction for FEV1 at 5 min and from 120 min to 240 min post-inhalation, whereas from 30 min to 60 min post-administration the drug interaction was additive. This study shows that aclidinium and formoterol can produce a significant synergistic interaction that may have a role also in the clinic setting.
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http://dx.doi.org/10.1016/j.rmed.2015.08.005DOI Listing
October 2015

Olodaterol + tiotropium bromide for the treatment of chronic obstructive pulmonary disease.

Expert Rev Clin Pharmacol 2015 ;8(5):529-39

a 1 Department of Systems Medicine, University of Rome Tor Vergata, Chair of Respiratory Medicine, Rome, Italy.

A solid scientific rationale and an increasing body of clinical evidence for combining a β2-agonist with an antimuscarinic agent in COPD fully support the opinion that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action. Tiotropium is an established choice for the management of patients with stable COPD, and olodaterol is a new effective and safe once-daily long-acting β2-agonist. The parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The large ongoing TOviTO Phase III trial program is documenting the efficacy and safety of olodaterol/tiotropium fixed dose combination delivered via the Respimat Soft Mist Inhaler as maintenance therapy in patients with moderate to very severe COPD. However, we must still know whether this fixed-dose combination will affect exacerbations and hospitalizations, and ultimately death, and also the precise estimates of its relative cardiovascular safety.
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http://dx.doi.org/10.1586/17512433.2015.1075389DOI Listing
April 2016

Pharmacological assessment of the onset of action of aclidinium and glycopyrronium versus tiotropium in COPD patients and human isolated bronchi.

Eur J Pharmacol 2015 Aug 5;761:383-90. Epub 2015 May 5.

Division of Respiratory Medicine, Department of Internal Medicine, University Hospital "Tor Vergata", Rome, Italy; Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Research Unit of Respiratory Clinical Pharmacology, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.
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http://dx.doi.org/10.1016/j.ejphar.2015.04.042DOI Listing
August 2015

Canakinumab for the treatment of chronic obstructive pulmonary disease.

Pulm Pharmacol Ther 2015 Apr 4;31:15-27. Epub 2015 Feb 4.

Department of Experimental Medicine, Second University of Naples, Naples, Italy.

COPD is a preventable and treatable disease associated with an enhanced chronic inflammatory response. In addition to chronic inflammation other mechanisms have been proposed that is likely to be involved in the development and progression of COPD. Recent evidence in the literature suggests a role for the inflammasome in the airway inflammation observed in COPD. Inflammasomes are intracellular multiprotein complexes that facilitate the autoactivation of the proinflammatory caspase-1 that in response to specific signals induces ultimately the release of the mature form of the inflammatory cytokines IL-1β and IL-18. In stable COPD was observed a higher production of IL-1, with levels further increases during exacerbations. IL-1 is strongly expressed by macrophage-monocyte. It seems that the activity of IL-1β in the lung induces a phenotype with typical characteristics of COPD consisting of lung inflammation, emphysema, and airway fibrosis. COPD could benefit from a targeted approach to the suppression of the inflammatory response, although an effective anti-inflammatory treatment is not yet available. Canakinumab, an anti-IL-1β monoclonal antibody, that binds to human IL-1β with high specificity and neutralizes its signaling, resulting in suppression of inflammation in patients with disorders of autoimmune origin, has been recently evaluated in inflammatory conditions such as COPD.
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http://dx.doi.org/10.1016/j.pupt.2015.01.005DOI Listing
April 2015

Autonomic system modification in Zen practitioners.

Indian J Med Sci 2013 Jul-Aug;67(7-8):161-7

U.O.C Geriatria e Medicina, COB, Viterbo, Italy.

Background: Meditation in its various forms is a traditional exercise with a potential benefit on well-being and health. On a psychosomatic level these exercises seem to improve the salutogenetic potential in man.Especially the cardiorespiratory interaction seems to play an important role since most meditation techniques make use of special low frequency breathing patterns regardless of whether they result from a deliberate guidance of breathing or other mechanisms, for example, the recitation of specific verse. During the different exercises of Zen meditation the depth and the duration of each respiratory cycle is determined only by the process of breathing. Respiratory manoeuvres during Zazen meditation may produce HR variability changes similar to those produces during biofeedback. Recognition that the respiratory sinus arrhythmia (RSA) was mediated by efferent vagal activity acting on the sinus node led investigators to attempt to quantify the fluctuations in R-R intervals that were related to breathing.

Materials And Methods: Nine Zen practitioners with five years of experience took part in the study. Autonomic nervous system function was evaluated by heart rate variability (HRV) analysis during 24-hours ECG recording during zen meditation and at rest.

Results: The data of this small observational study confirm that ZaZen breathing falls within the range of low frequency HR spectral bands. Our data suggest that the modification of HR spectral power remained also in normal day when the subject have a normal breathing.

Conclusion: We suggest that the changes in the breathing rate might modify the chemoreflex and the continuous practice in slow breathing can reduce chemoreflex. This change in the automonic control of respiration can be permanent with a resetting of endogenous circulatory rhythms.
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http://dx.doi.org/10.4103/0019-5359.125877DOI Listing
April 2015

Does exercise test modality influence dyspnoea perception in obese patients with COPD?

Eur Respir J 2014 Jun 5;43(6):1621-30. Epub 2013 Dec 5.

Respiratory Investigation Unit, Dept of Medicine, Queen's University and Kingston General Hospital, Kingston, ON

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated. We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean ± sd body mass index 36.4 ± 5.0 kg·m(-2)) patients with COPD (forced expiratory volume in 1 s 60 ± 11% predicted). Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p<0.01). Cycle testing was associated with a higher respiratory exchange ratio (p<0.01), earlier ventilatory threshold (p<0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships. Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings.
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http://dx.doi.org/10.1183/09031936.00151513DOI Listing
June 2014

Effect of indacaterol on arterial blood gases in patients suffering from acute exacerbation of COPD.

Respir Med 2014 Feb 5;108(2):307-13. Epub 2013 Nov 5.

Department of System Medicine, University of Rome 'Tor Vergata', Rome, Italy; Department of Internal Medicine, 'Tor Vergata' Polyclinic Hospital, Rome, Italy. Electronic address:

Aim: The administration of β2-agonists to patients with airways obstruction often results in transient decrease in PaO2 despite concomitant bronchodilation. This effect is potentially dangerous for patients suffering from acute exacerbation of COPD (AECOPD). In this study, we investigated the effect of indacaterol 150 μg and 300 μg on the arterial blood gas tensions of hospitalised patients with AECOPD.

Methods: We explored the acute effects on arterial blood gases and spirometry of two doses of indacaterol Breezhaler (150 and 300 μg) in 12 patients hospitalised because of an AECOPD in 2 non-consecutive days under open-label, randomized, crossover conditions, with blind evaluation. Blood specimens were taken just before the inhalation and at 15, 30, 60, 120, 240 and 360 min after inhalation of each treatment, and spirometry was performed at the same time points.

Results: Both doses of indacaterol did not cause significant changes in blood gases, although some patients with relatively well-preserved PaO2 presented transient episodes of oxygen desaturation that normalize spontaneously in a very short time. Moreover, they induced a significant mean increase in FEV1 and FVC, although the improvement caused by indacaterol 300 μg was larger.

Conclusions: Indacaterol up to 300 μg is a potent bronchodilator that may induce small, transient decrease in PaO2 mainly in patients with relatively well-preserved PaO2. There appeared to be no clinical consequences of these PaO2 abnormalities in patients suffering from AECOPD.
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http://dx.doi.org/10.1016/j.rmed.2013.10.022DOI Listing
February 2014

A 6MWT index to predict O2 flow correcting exercise induced SpO2 desaturation in ILD.

Respir Med 2013 Dec 10;107(12):2014-21. Epub 2013 Oct 10.

Respiratory Diseases Unit, Department of Medicine, "Tor Vergata" University Hospital, Rome, Italy. Electronic address:

Introduction: Ambulatory oxygen (O2) is prescribed to interstitial lung disease (ILD) patients with mild hypoxemia, breathlessness and dyspnea on exertion. Oxygen titration is generally done with the 6 minute walk test (6MWT) to determine the O2 flow preventing oxygen saturation by pulse oximetry (SpO2) from falling below 88%. His study was designed to generate a 6MWT index predicting the O2 flow allowing completion of the 6MWT without oxygen desaturation.

Methods: Oxygen titration data from a group of 66 ILD patients and 30 controls, were used to generate the algorithm determining an index (O2-GAP) predicting oxygen flow required to complete a 6MWT without desaturation below 88%. This index was validated in a group of 93 ILD patients.

Results: The O2-GAP index, as obtained from the derivation population, (r(2) = 0.97, p < 0.001) was shown to correctly predict the oxygen flow required to complete the 6MWT without SpO2 falling below 88% validated in the validation population (r(2) = 0.842; p < 0.001).

Conclusions: The O2-GAP index appears to be a useful tool to titrate ambulatory O2 with a single 6MWT on room air in ILD patients with breathlessness and dyspnea on exertion.
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http://dx.doi.org/10.1016/j.rmed.2013.10.002DOI Listing
December 2013

Effect of an additional dose of indacaterol in COPD patients under regular treatment with indacaterol.

Respir Med 2013 Jan 18;107(1):107-11. Epub 2012 Oct 18.

Department of System Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.

Aim: In this randomized, double-blind, crossover study, we explored the acute effects on respiratory function and safety of an additional dose of indacaterol 150 μg in stable COPD patients regularly treated with a conventional dose of indacaterol 150 μg.

Methods: On two non-consecutive days, patients inhaled indacaterol 150 μg. After 180 min, they inhaled an additional dose of indacaterol 150 μg or placebo. Lung function, oxygen saturation by pulse oximetry (SpO(2)) and heart rate were measured before the first drug administration and up to 360 min thereafter.

Results: In both treatment groups, indacaterol induced a significant (P < 0.05) bronchodilation during all the study time. The difference between the FEV(1) AUCs(0-180 min) was not statistically significant (P = 0.971). On the contrary, the difference between the FEV(1) AUCs(180-360 min) was significant (P < 0.0001). However, only 8 out of 20 patients showed a further increase of at least 100 ml from the peak obtained after the first administration of indacaterol 150 μg with the second dose of 150 μg. Indacaterol 150 μg induced a modest but significant decrease in SpO(2) up to 60 min and a second dose of indacaterol 150 μg significantly decreased the SpO(2) mean value up to 360 min.

Conclusion: This study suggests that it is reasonable and safe to increase the dose of indacaterol in those stable COPD patients who are under regular therapy with indacaterol 150 μg from which they do not draw the maximum benefit because they are unable to perceive bronchodilation. However, only a minority of patients seem to benefit from this dose escalation, at least in terms of spirometric improvement.
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http://dx.doi.org/10.1016/j.rmed.2012.09.022DOI Listing
January 2013

Evolution of dyspnea during exercise in chronic obstructive pulmonary disease: impact of critical volume constraints.

Am J Respir Crit Care Med 2011 Dec 1;184(12):1367-73. Epub 2011 Sep 1.

Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) primarily describe their exertional dyspnea using descriptors alluding to increased effort or work of breathing and unsatisfied inspiration or inspiratory difficulty.

Objectives: The purpose of this study was to examine the impact of changes in dynamic respiratory mechanics during incremental (INCR) and high-intensity constant work-rate (CWR) cycle exercise on the evolution of dyspnea intensity and its major qualitative dimensions in patients with moderate-to-severe COPD.

Methods: Sixteen subjects with COPD performed symptom-limited INCR and CWR cycle exercise tests. Measurements included dyspnea intensity and qualitative descriptors, breathing pattern, operating lung volumes, and esophageal pressure (Pes).

Measurements And Main Results: During both exercise tests, there was an inflection in the relation between tidal volume (Vt) and ventilation. This inflection occurred significantly earlier in time during CWR versus INCR exercise but at a similar ventilation, Vt, and tidal Pes swing. Beyond this inflection, there was no further change in Vt despite a continued increase in ventilation and tidal Pes. During both tests, "work and effort" was the dominant dyspnea descriptor selected up to the inflection point, whereas after this point dyspnea intensity and the selection frequency of "unsatisfied inspiration" rose sharply.

Conclusions: Regardless of the exercise test protocol, the inflection (or plateau) in the Vt response marked the point where dyspnea intensity rose abruptly and there was a transition in the dominant qualitative descriptor choice from "work and effort" to "unsatisfied inspiration." Intensity and quality of dyspnea evolve separately and are strongly influenced by mechanical constraints on Vt expansion during exercise in COPD.
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http://dx.doi.org/10.1164/rccm.201106-1128OCDOI Listing
December 2011

Effect of obesity on respiratory mechanics during rest and exercise in COPD.

J Appl Physiol (1985) 2011 Jul 24;111(1):10-9. Epub 2011 Feb 24.

Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.

The presence of obesity in COPD appears not to be a disadvantage with respect to dyspnea and weight-supported cycle exercise performance. We hypothesized that one explanation for this might be that the volume-reducing effects of obesity convey mechanical and respiratory muscle function advantages. Twelve obese chronic obstructive pulmonary disease (COPD) (OB) [forced expiratory volume in 1 s (FEV(1)) = 60%predicted; body mass index (BMI) = 32 ± 1 kg/m(2); mean ± SD] and 12 age-matched, normal-weight COPD (NW) (FEV(1) = 59%predicted; BMI = 23 ± 2 kg/m(2)) subjects were compared at rest and during symptom-limited constant-work-rate exercise at 75% of their maximum. Measurements included pulmonary function tests, operating lung volumes, esophageal pressure, and gastric pressure. OB vs. NW had a reduced total lung capacity (109 vs. 124%predicted; P < 0.05) and resting end-expiratory lung volume (130 vs. 158%predicted; P < 0.05). At rest, there was no difference in respiratory muscle strength but OB had greater (P < 0.05) static recoil and intra-abdominal pressures than NW. Peak ventilation, oxygen consumption, and exercise endurance times were similar in OB and NW. Pulmonary resistance fell (P < 0.05) at the onset of exercise in OB but not in NW. Resting inspiratory capacity, dyspnea/ventilation plots, and the ratio of respiratory muscle effort to tidal volume displacement were similar, as was the dynamic performance of the respiratory muscles including the diaphragm. In conclusion, the lack of increase in dyspnea and exercise intolerance in OB vs. NW could not be attributed to improvement in respiratory muscle function. Potential contributory factors included alterations in the elastic properties of the lungs, raised intra-abdominal pressures, reduced lung hyperinflation, and preserved inspiratory capacity.
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http://dx.doi.org/10.1152/japplphysiol.01131.2010DOI Listing
July 2011

Exertional dyspnea in chronic obstructive pulmonary disease: mechanisms and treatment approaches.

Curr Opin Pulm Med 2010 Mar;16(2):144-9

Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.

Purpose Of Review: The purpose of this review is to identify new advances in our understanding of dyspnea in patients with chronic obstructive pulmonary disease (COPD). Specifically, we highlight new scientific discoveries concerning the language of dyspnea, its underlying mechanisms and its clinical management.

Recent Findings: Recent studies have confirmed that dyspnea is multidimensional and that sensory intensity and quality dimensions of the symptom are readily distinguishable by the individual. When respiratory discomfort is sufficiently unpleasant in COPD, an emotive response is evoked which encompasses feelings of fear and anxiety. Such descriptors appear to be unique to the disease state and are rarely reported in health. Recent brain imaging studies have proposed a central role of the limbic and paralimbic systems in the genesis of perceived dyspnea or its affective component. There is new indirect evidence that the elaboration of endogenous opioids may modulate dyspnea intensity during exercise in COPD. New physiological studies in COPD have provided novel insights into mechanisms of dyspnea both in early disease and in the setting of coexistent obesity.

Summary: The effective management of dyspnea in COPD remains a significant challenge for caregivers but recent treatment innovations such as helium-oxygen, inhaled furosemide and breathing feedback techniques have yielded early positive results.
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http://dx.doi.org/10.1097/MCP.0b013e328334a728DOI Listing
March 2010

Effects of obesity on perceptual and mechanical responses to bronchoconstriction in asthma.

Am J Respir Crit Care Med 2010 Jan 12;181(2):125-33. Epub 2009 Nov 12.

Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.

Rationale: The influence of obesity on the perception of respiratory discomfort during acute bronchoconstriction in asthma is unknown.

Objectives: We hypothesized that the respiratory impairment associated with an increased body mass index (BMI) would predispose to greater perceived symptom intensity during acute airway narrowing. We therefore compared relationships between induced changes in dyspnea intensity and lung function during methacholine (MCh) bronchoprovocation in obese (OBA) and normal-weight (NWA) individuals with asthma of mild to moderate severity.

Methods: High-dose MCh challenge tests to a maximum 50% decrease in FEV(1) were conducted in 51 NWA (BMI, 18.5-24.9 kg/m(2); 29% male) and 45 OBA (BMI, 30.1-51.4 kg/m(2); 33% male) between 20 and 60 years of age. Serial spirometry, inspiratory capacity (IC), plethysmographic end-expiratory lung volume (EELV) and dyspnea intensity using the Borg scale were measured throughout bronchoprovocation.

Measurements And Main Results: Spirometry and airway sensitivity were similar in both groups; baseline EELV was lower (P < 0.0005) and IC was higher (P = 0.007) in OBA compared with NWA. From baseline to PC(20), EELV increased more in OBA (20% predicted) than NWA (13% predicted) (P = 0.008) with concomitant greater reductions in IC (P < 0.0005). Dyspnea ratings were not different for a given FEV(1) or IC across groups. By mixed effects regression analysis, relationships between induced dyspnea and changes in lung function parameters were not influenced by BMI, sex, or their interaction.

Conclusions: Perceptual responses to MCh-induced bronchoconstriction and lung hyperinflation were similar in obese and normal-weight individuals with asthma despite significant group differences in baseline lung volumes.
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http://dx.doi.org/10.1164/rccm.200906-0934OCDOI Listing
January 2010

Combined effects of obesity and chronic obstructive pulmonary disease on dyspnea and exercise tolerance.

Am J Respir Crit Care Med 2009 Nov;180(10):964-71

Respiratory Investigation Unit, Department of Medicine, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.

Rationale: Severity of lung hyperinflation is known to influence the extent of dyspnea and exercise intolerance among patients with chronic obstructive pulmonary disease (COPD) with similar degrees of airway obstruction. Lung volume components are consistently affected by body mass index (BMI) in health and in disease.

Objectives: To explore the complex interactions between obesity, lung hyperinflation, dyspnea, and exercise performance in COPD.

Methods: We compared dyspnea intensity ratings and ventilatory responses (breathing pattern, operating lung volumes, and gas exchange) during symptom-limited incremental cycle exercise in well-characterized groups of 18 obese (mean BMI +/- SD, 35 +/- 4 kg/m(2)) and 18 normal-weight (mean BMI +/- SD, 22 +/- 2 kg/m(2)) patients with moderate to severe COPD.

Measurements And Main Results: Groups were well matched for FEV(1) (mean 49% predicted) and diffusing capacity (means >70% predicted), but resting lung hyperinflation (end-expiratory lung volume [EELV]) was significantly reduced in association with increasing BMI (P < 0.005). In the obese patients, peak symptom-limited oxygen uptake was increased (P < 0.01) and dyspnea ratings at a standardized ventilation were decreased (P < 0.01) compared with normal-weight patients. Ratings of dyspnea intensity at a standardized ventilation during exercise correlated well with the concurrent dynamic EELV/total lung capacity (TLC) ratio (r = 0.68; P < 0.00001) and with the resting EELV/TLC (r = 0.67; P < 0.00001).

Conclusions: The combined mechanical effects of obesity and COPD reduced operating lung volumes at rest and throughout exercise with favorable influences on dyspnea perception and peak oxygen uptake during cycle ergometry.
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http://dx.doi.org/10.1164/rccm.200904-0530OCDOI Listing
November 2009

Bronchodilator effect on ventilatory, pulmonary gas exchange, and heart rate kinetics during high-intensity exercise in COPD.

Eur J Appl Physiol 2009 Dec 27;107(6):633-43. Epub 2009 Aug 27.

Respiratory Investigation Unit, Department of Medicine, Kingston General Hospital, Queen's University, 102 Stuart Street, Kingston, ON K7L 2V6, Canada.

Respiratory mechanical abnormalities in patients with chronic obstructive pulmonary disease (COPD) may impair cardiodynamic responses and convective oxygen delivery during exercise, resulting in slower ventilatory, pulmonary gas exchange (PGE), and heart rate (HR) kinetics compared with normal. We reasoned that bronchodilators and the attendant reduction of operating lung volumes should accelerate ventilatory, PGE, and HR kinetics in the transition from rest to high-intensity exercise. Twelve clinically stable COPD patients undertook constant-work rate cycle testing at 75% of each individual's maximum work capacity after receiving either combined nebulized bronchodilators (BD) or placebo (PL), randomly. Mean response time (MRT) and amplitude of slow component for oxygen uptake (V'O(2)), carbon dioxide production (V'CO(2)), ventilation (V'(E)), and HR together with operating dynamic end-expiratory lung volume (EELV) were measured. Resting and exercise EELV decreased significantly by 0.38 L after BD compared with PL. After BD, V'O(2), V'CO(2), V'(E), and HR MRT accelerated (p < 0.05) by an average of 12, 22, 27, and 22 s, respectively (i.e., 15, 18, 22 and 27%, respectively). The slow component for V'O(2) declined by an average of 55 ml/min compared with PL. Speeded MRT for V'O(2) correlated with indices of reduced lung hyperinflation, such as resting EELV (r = -0.64, p = 0.025) and EELV at isotime (r = -0.77, p = 0.0032). The results confirm an important interaction between abnormal dynamic respiratory mechanics and indices of cardio-circulatory function in the rest-to-exercise transition in COPD patients.
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http://dx.doi.org/10.1007/s00421-009-1169-4DOI Listing
December 2009

Mechanisms of activity-related dyspnea in pulmonary diseases.

Respir Physiol Neurobiol 2009 May 7;167(1):116-32. Epub 2009 Feb 7.

Progressive activity-related dyspnea dominates the clinical presentation of patients afflicted by chronic obstructive and restrictive lung diseases. This symptom invariably leads to activity limitation, global skeletal muscle deconditioning and an impoverished quality of life. The effective management of exertional dyspnea remains an elusive goal but our understanding of the nature and mechanisms of this distressing symptom continues to grow. Refinements in psychophysical measurement of the sensory intensity and quality of dyspnea during laboratory clinical cardiopulmonary exercise testing (CPET) have provided new insights into causation. In this review, we focus on what is known about the physiological mechanisms of dyspnea during physical exertion in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Although these conditions are pathologically diverse, perceptual and ventilatory responses to exercise are remarkably similar among patients with these two conditions. In both patient groups, dyspnea intensity is increased at any given ventilation compared with age-matched healthy individuals; at the limits of tolerance, most patients predominantly select qualitative descriptors that allude to perceptions of "increased respiratory effort" and "unsatisfied inspiration." Common abnormal physiological responses to CPET across conditions include: (1) increased central respiratory drive secondary to pulmonary gas exchange and metabolic derangements, (2) abnormal "restrictive" constraints on tidal volume expansion with earlier development of critical mechanical limitation of ventilation and (3) an increasing disparity (as exercise proceeds) between the magnitude of contractile respiratory muscle effort and the thoracic volume displacement achieved. Reductionist experimental approaches that attempt to partition, or isolate, the contribution of central and multiple peripheral sensory afferent systems to activity-induced dyspnea have met with limited success. Integrative approaches which explore the possible neurophysiological mechanisms involved in the two dominant qualitative descriptors of activity-related dyspnea in both diseases may prove to be more fruitful. In this review, we present a hypothetical model for exertional dyspnea that is based on current neurophysiological constructs that have been rigorously developed to explain the origins of perceptions of "effort," "air hunger" and the accompanying affective "distress" response.
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http://dx.doi.org/10.1016/j.resp.2009.01.010DOI Listing
May 2009

Estimation of the exercise ventilatory compensation point by the analysis of the relationship between minute ventilation and heart rate.

Eur J Appl Physiol 2008 Sep 14;104(1):87-94. Epub 2008 Jun 14.

Dipartimento di Medicina Clinica, Servizio di Fisiopatologia Respiratoria, Università La Sapienza, viale dell' Università 37, Rome, Italy.

Cardiopulmonary exercise test is the gold standard for the identification of the ventilatory compensation point (VCP), an important threshold for exercise training prescription. We hypothesized that changes in the slope of increment in minute ventilation (V'(E)) over heart rate (HR) during incremental exercise can be utilized, as alternative to the ventilatory equivalents method, for VCP detection. In 14 healthy subjects (ten males, four females, age 31 +/- 10 SD) we studied the ventilatory, cardiovascular and gas exchange adaptations during two incremental cycle ergometer exercise: (F) fast work rate increments (30-20 watt/min, M-F), (S) slow work rate increments (15-10 watt/min, M-F). A good between-method agreement in VCP detection in terms of oxygen uptake (V'O(2)) was found in both F and S protocols (F: -7 +/- 118 V'O(2) ml/min; S: -36 +/- 144 V'O(2) ml/min). VCP occurred at the same percentage of peak V'O(2) in both protocols. The changes in the V'(E) versus HR slope during incremental exercise can be used to detect the VCP as alternative to the ventilatory equivalents method.
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http://dx.doi.org/10.1007/s00421-008-0777-8DOI Listing
September 2008