Letter to the Editor
Effect of Drug-Targeting Nebulization on Lung Delivery
Efecto de la nebulización dirigida de fármacos en la administración pulmonar
Gregory Reychlera,b,
, Anne-Sophie Aubriotc,d, Julien Masqueliere, G. Giulio Mucciolie, Giuseppe Liistroa,b
Corresponding author
a Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Bruselas, Belgium
b Service de Pneumologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium
c Department of Physical Medicine and Rehabilitation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium
d Department of Pediatry, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium
e Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium
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Giulio Muccioli, Giuseppe Liistro" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Gregory" "apellidos" => "Reychler" "email" => array:1 [ 0 => "Gregory.reychler@uclouvain.be" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Anne-Sophie" "apellidos" => "Aubriot" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 2 => array:3 [ "nombre" => "Julien" "apellidos" => "Masquelier" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 3 => array:3 [ "nombre" => "G. Giulio" "apellidos" => "Muccioli" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 4 => array:3 [ "nombre" => "Giuseppe" "apellidos" => "Liistro" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Bruselas, Belgium" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Service de Pneumologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Physical Medicine and Rehabilitation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Pediatry, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruselas, Belgium" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efecto de la nebulización dirigida de fármacos en la administración pulmonar" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1389 "Ancho" => 1464 "Tamanyo" => 67874 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Nebulization delivery modes during one inspiratory cycle.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">It has been difficult to develop more effective nebulizers for the improved delivery of drugs directly to the lungs. Adaptive nebulizers were designed for the administration of drugs at a specific time during inspiration, depending on the intended target (drug-targeting nebulization). Controlled inhalation nebulizers, such as AKITA<span class="elsevierStyleSup">®</span>, have recently become another addition to adaptive aerosol delivery systems.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The aim of our study was to measure the inhaled dose and pulmonary bioavailability obtained from drug-targeting nebulization, compared to conventional continuous nebulization.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We used the AKITA<span class="elsevierStyleSup">®</span> delivery device (Activaero; Germany) that provides individualized, controlled flow and inhalation volumes in several puffs. Aerosolized drug delivery was either continuous or targeted (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) during each 4-s controlled inhalation. The number of inhalations was 43 or 86, respectively.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The inhaled dose of a solution of amikacin (125<span class="elsevierStyleHsp" style=""></span>mg/ml) was measured <span class="elsevierStyleItalic">in vitro</span> using a residual gravimetric method.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Five healthy non-smoking male volunteers (mean age 27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.7 years) were selected, and approval was obtained from the ethics committee.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Subjects were randomized to receive a solution of salbutamol (GlaxoSmithKline, Belgium) (625<span class="elsevierStyleHsp" style=""></span>mg/ml) <span class="elsevierStyleItalic">via</span> continuous or targeted nebulization.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Subjects swallowed 100<span class="elsevierStyleHsp" style=""></span>ml of activated charcoal before and after nebulization (Carbomix, Norit, Netherlands). Urine samples were obtained before nebulization and 30<span class="elsevierStyleHsp" style=""></span>min after (Cu-30), and then from each spontaneous micturition and 240<span class="elsevierStyleHsp" style=""></span>min (Cu-240) after the start of nebulization. The volume of each micturition was measured.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Salbutamol levels in urine were measured in triplicate by HPLC.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The amount of salbutamol excreted in urine (Cu) was calculated by multiplying the concentration by the volume of each sample. Pulmonary bioavailability was compared using the Cu-30 sample.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Mean anthropometric and spirometric values were as follows: height 177.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.8<span class="elsevierStyleHsp" style=""></span>cm and weight 80.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>19.6<span class="elsevierStyleHsp" style=""></span>kg, FVC 103.7%<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>16.8% of the predicted value and FEV1 100.3%<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.5% of the predicted value.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The inhaled dose was not significantly different (15.8% <span class="elsevierStyleItalic">versus</span> 16.5%, respectively, <span class="elsevierStyleItalic">p</span>=0.975) but the amount of drug delivered with the continuous nebulization method was twice that of the targeted method (<span class="elsevierStyleItalic">p</span><0.001).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The excreted amounts of salbutamol are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Cu-30 was similar for both delivery systems (<span class="elsevierStyleItalic">p</span>=0.947). The accumulated amount of salbutamol excreted in urine was significantly higher with the targeted nebulization system (<span class="elsevierStyleItalic">p</span><0.05).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Pulmonary bioavailability of nebulized salbutamol is a reproducible measurement for predicting drug deposition in the lung<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and for determining the amount of drug that is provided to the body <span class="elsevierStyleItalic">via</span> the pulmonary route and rapidly excreted in the urine. Concentrations may be overestimated in healthy individuals,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> but this does not affect the comparison of the delivery methods. Our results confirm that the AKITA<span class="elsevierStyleSup">®</span> device delivers a greater amount of drug than other devices, with a pulmonary bioavailability approximately twice that previously described with 8 conventional nebulizers with different flows.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However, drug-targeting nebulization did not affect pulmonary bioavailability compared to continuous administration. A significantly higher accumulated amount of excreted salbutamol was recovered from subjects using the targeted delivery device.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Further studies in radio-labelled aerosols will be needed to clarify the effect of targeted nebulization on drug deposition in the lungs. To conclude, drug-targeted nebulization does not change pulmonary bioavailability in healthy individuals but it does reduce the amount of drug delivered.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Clinical Trial: <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01913184">NCT01913184</a>.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Authorship</span><p id="par0065" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">a)</span><p id="par0070" class="elsevierStylePara elsevierViewall">Study concept and design or data collection, analysis or interpretation: Gregory Reychler, Anne-Sophie Aubriot, Julien Masquelier and G. Giulio Muccioli.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">b)</span><p id="par0075" class="elsevierStylePara elsevierViewall">Preliminary draft of the article or critical review of significant intellectual content: Gregory Reychler, G. Giulio Muccioli and Giuseppe Liistro.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">c)</span><p id="par0080" class="elsevierStylePara elsevierViewall">Final approval of version submitted for publication: Gregory Reychler, Anne-Sophie Aubriot, Julien Masquelier, G. Giulio Muccioli and Giuseppe Liistro.</p></li></ul></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of Interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">No conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Authorship" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of Interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Reychler G, Aubriot AS, Masquelier J, Muccioli GG, Liistro G. Efecto de la nebulización dirigida de fármacos en la administración pulmonar. Arch Bronconeumol. 2014;50:500–501.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1389 "Ancho" => 1464 "Tamanyo" => 67874 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Nebulization delivery modes during one inspiratory cycle.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Results expressed as mean±standard deviation.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Continuous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Discontinuous \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cu-30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.69±31.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35.56±28.39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cu-60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.59±15.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.72±37.24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cu-240 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.08±25.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84.89±36.47 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Accumulative amount \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">118.36±47.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">172.18±46.82<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab578276.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005"><span class="elsevierStyleItalic">p</span><0.05.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Excreted Salbutamol (mcg) Retrieved After Nebulization With the Continuous or Discontinuous Delivery System in 5 Healthy Individuals.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Total deposition of therapeutic particles during spontaneous and controlled inhalations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P. Brand" 1 => "I. Friemel" 2 => "T. Meyer" 3 => "H. Schulz" 4 => "J. Heyder" 5 => "K. Haubetainger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1520-6017(200006)89:6<724::AID-JPS3>3.0.CO;2-B" "Revista" => array:6 [ "tituloSerie" => "J Pharm Sci" "fecha" => "2000" "volumen" => "89" "paginaInicial" => "724" "paginaFinal" => "731" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10824130" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Residual gravimetric method to measure nebulizer output" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.L. Vecellio" 1 => "D. Grimbert" 2 => "J. Bordenave" 3 => "G. Benoit" 4 => "Y. Furet" 5 => "B. 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Chrystyn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpba.2009.04.006" "Revista" => array:6 [ "tituloSerie" => "J Pharm Biomed Anal" "fecha" => "2009" "volumen" => "50" "paginaInicial" => "175" "paginaFinal" => "182" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19443162" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An investigation of in vitro/in vivo correlations for salbutamol nebulized by eight systems" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "V.L. Silkstone" 1 => "J.H. Dennis" 2 => "C.A. Pieron" 3 => "H. Chrystyn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/089426802760292591" "Revista" => array:6 [ "tituloSerie" => "J Aerosol Med" "fecha" => "2002" "volumen" => "15" "paginaInicial" => "251" "paginaFinal" => "259" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12396413" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Melchor" 1 => "M.F. Biddiscombe" 2 => "V.H. Mak" 3 => "M.D. Short" 4 => "S.G. Spiro" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Thorax" "fecha" => "1993" "volumen" => "48" "paginaInicial" => "506" "paginaFinal" => "511" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8322237" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673606688466" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005000000011/v1_201410310135/S1579212914002572/v1_201410310135/en/main.assets" "Apartado" => array:4 [ "identificador" => "14576" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Letters to the editor" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005000000011/v1_201410310135/S1579212914002572/v1_201410310135/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212914002572?idApp=UINPBA00003Z" ]
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