Scientific letter
Carglumic acid (Carbaglu®) treatment in hyperammonemia post liver transplantation
Tratamiento con ácido carglúmico (Carbaglu®) en la hiperamoniemia post transplante hepático
Francisco Arrietaa,b,
, Amaya Belanger-Quintanac, Luis Gajated, Javier Graue, Rosario Pintorf
Corresponding author
a Centro de Investigación Biomédica en Red-Fisiopatología de Obesidad y Nutrición, (CIBERobn), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain
b Department of Endocrinology & Nutrition and Metabolic Unit Hospital Universitario Ramón y Cajal, Madrid, Spain
c Department of Pediatrics, Nutrition and Metabolic Unit, Hospital Universitario Ramón y Cajal, Madrid, Spain
d Department of Anesthesia and Reanimation, University Hospital Ramón y Cajal, Spain
e Gastroenterology Department, Hospital Universitario Ramón y Cajal, Spain
f Pharmacy Department, University Hospital Ramón y Cajal, Madrid, Spain
Read
1364
Timeswas read the article
233
Total PDF
1131
Total HTML
Share statistics
array:23 [ "pii" => "S2530018020300147" "issn" => "25300180" "doi" => "10.1016/j.endien.2020.02.002" "estado" => "S300" "fechaPublicacion" => "2020-02-01" "aid" => "956" "copyright" => "SEEN and SED" "copyrightAnyo" => "2019" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Endocrinol Diabetes Nutr. 2020;67:148-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:17 [ "pii" => "S2530018020300123" "issn" => "25300180" "doi" => "10.1016/j.endien.2020.02.001" "estado" => "S300" "fechaPublicacion" => "2020-02-01" "aid" => "934" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Endocrinol Diabetes Nutr. 2020;67:149-51" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Current situation of adult women with Turner syndrome in Spain" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "149" "paginaFinal" => "151" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Situación actual de mujeres adultas afectas de Síndrome de Turner en España" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elena Godoy-Molina, María del Carmen López-Castillo, Laura Galán-Bueno, Estrella Morejón-García, Juan Pedro López-Siguero" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Elena" "apellidos" => "Godoy-Molina" ] 1 => array:2 [ "nombre" => "María del Carmen" "apellidos" => "López-Castillo" ] 2 => array:2 [ "nombre" => "Laura" "apellidos" => "Galán-Bueno" ] 3 => array:2 [ "nombre" => "Estrella" "apellidos" => "Morejón-García" ] 4 => array:2 [ "nombre" => "Juan Pedro" "apellidos" => "López-Siguero" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018020300123?idApp=UINPBA00004N" "url" => "/25300180/0000006700000002/v1_202004190644/S2530018020300123/v1_202004190644/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2530018020300159" "issn" => "25300180" "doi" => "10.1016/j.endien.2020.03.001" "estado" => "S300" "fechaPublicacion" => "2020-02-01" "aid" => "971" "copyright" => "SEEN and SED" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Endocrinol Diabetes Nutr. 2020;67:137-47" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Maturity-onset diabetes of the young: From a molecular basis perspective toward the clinical phenotype and proper management" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "137" "paginaFinal" => "147" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "<span class="elsevierStyleItalic">Maturity onset diabetes of the young</span>: de la base molecular al fenotipo clínico y el manejo adecuado" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Ref. <a class="elsevierStyleCrossRef" href="#bib0610">53</a>." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1034 "Ancho" => 1667 "Tamanyo" => 149684 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Sulfonylurea receptor (SUR) components: 1 – SUR encoded by ABCC8 gene; 2 – potassium voltage-gated channel; Kir 6.20 – encoded by subfamily J member 11 (KCNJ11) gene.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sofia Castro Oliveira, João Sérgio Neves, Antonio Pérez, Davide Carvalho" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Sofia Castro" "apellidos" => "Oliveira" ] 1 => array:2 [ "nombre" => "João Sérgio" "apellidos" => "Neves" ] 2 => array:2 [ "nombre" => "Antonio" "apellidos" => "Pérez" ] 3 => array:2 [ "nombre" => "Davide" "apellidos" => "Carvalho" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018020300159?idApp=UINPBA00004N" "url" => "/25300180/0000006700000002/v1_202004190644/S2530018020300159/v1_202004190644/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Carglumic acid (Carbaglu®) treatment in hyperammonemia post liver transplantation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "148" "paginaFinal" => "149" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Francisco Arrieta, Amaya Belanger-Quintana, Luis Gajate, Javier Grau, Rosario Pintor" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Francisco" "apellidos" => "Arrieta" "email" => array:1 [ 0 => "francisco.arrieta@salud.madrid.org" ] "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" => "Amaya" "apellidos" => "Belanger-Quintana" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Luis" "apellidos" => "Gajate" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "Javier" "apellidos" => "Grau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 4 => array:3 [ "nombre" => "Rosario" "apellidos" => "Pintor" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red-Fisiopatología de Obesidad y Nutrición, (CIBERobn), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Endocrinology & Nutrition and Metabolic Unit Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Pediatrics, Nutrition and Metabolic Unit, Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Anesthesia and Reanimation, University Hospital Ramón y Cajal, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Gastroenterology Department, Hospital Universitario Ramón y Cajal, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Pharmacy Department, University Hospital Ramón y Cajal, Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento con ácido carglúmico (Carbaglu®) en la hiperamoniemia post transplante hepático" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 828 "Ancho" => 1520 "Tamanyo" => 88904 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Urea cycle.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We report the case of a male patient presenting with hyperammonemia after liver transplantation that was successfully reduced after treatment with carglumic acid and <span class="elsevierStyleSmallCaps">l</span>-arginine. Carglumic acid can be a useful tool to reduce high ammonia levels that frequently appear after liver transplantation.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case report</span><p id="par0010" class="elsevierStylePara elsevierViewall">Our patient is a 60-year-old male who received a first liver transplant to remove a hepatocellular carcinoma due to a virus B infection. He received the liver of an 80-year-old donor who had a double venous system and poor blood flow, which hampered the operation. In the first 48<span class="elsevierStyleHsp" style=""></span>h he had a graft dysfunction secondary to ischemia. While waiting an urgent retransplantation procedure, he began to manifest encephalopathic symptoms. His ammonia levels were found to be 155<span class="elsevierStyleHsp" style=""></span>μmol/L (normal <<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>μmol/L), but no measures were undertaken. He then received parenteral nutrition containing 8<span class="elsevierStyleHsp" style=""></span>g of nitrogen per day. Given his progressive neurological impairment, 12<span class="elsevierStyleHsp" style=""></span>h later ammonia levels were measured again and had reached 199<span class="elsevierStyleHsp" style=""></span>μmol/L. The inborn errors of metabolism specialist was contacted, exogenous protein nutrition was stopped and pharmacological treatment was initiated with 5<span class="elsevierStyleHsp" style=""></span>g of arginine and 2<span class="elsevierStyleHsp" style=""></span>g of carglumic acid administered via a nasogastric tube. In the follow-up blood test performed 3<span class="elsevierStyleHsp" style=""></span>h later, ammonia levels had decreased to 122<span class="elsevierStyleHsp" style=""></span>μmol/L, thus ruling out the need for dialysis or other drugs. A second course of 3<span class="elsevierStyleHsp" style=""></span>g of arginine and 1<span class="elsevierStyleHsp" style=""></span>g of carglumic acid achieved a further reduction of ammonia levels to 98<span class="elsevierStyleHsp" style=""></span>μmol/L 6<span class="elsevierStyleHsp" style=""></span>h after the initiation of treatment. The patient regained consciousness. In the following hours he received his second liver transplant. His ammonia levels after surgery were 78<span class="elsevierStyleHsp" style=""></span>μmol//L and it was decided to maintain treatment with 3<span class="elsevierStyleHsp" style=""></span>g of arginine every 8<span class="elsevierStyleHsp" style=""></span>h until 48<span class="elsevierStyleHsp" style=""></span>h later, by which time the patient had begun normal nutrition and had normal ammonia levels.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Discussion</span><p id="par0015" class="elsevierStylePara elsevierViewall">Following liver transplantation, hyperammonemia is a frequent complication and it is due to the inability to eliminate ammonia through ureagenesis during the time the patient has no functional liver before, during and in the early post-implantation stages. After transplantation, the urea cycle is less effective because of a defect in glutamate synthetase activity<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">1,2</span></a> but we believe it is also due to a secondary N-acetyl glutamate synthase (NAGS) deficiency as a result of possible acetyl-CoA depletion. A transplanted liver is invariably subjected to ischemic injury due to the transient lack of blood perfusion during transportation <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a> and, as in our case, due to surgical complications. Ischemia depletes hepatocyte stores of ATP<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> since, in the absence of aerobic respiration, mitochondrial oxidation of the enzymatic cofactors NADH and FADH2 does not take place. Lack of respiration also prevents the generation of acetylCoA from aerobic glycolysis or from beta-oxidation (since acylCoa dehydrogenase is FAD dependent), which is likely to promote an overall acetylCoA depletion in hepatocytes. As acetylCoA is one of the two substrates of NAGS, its deficiency induces a lack of NAGS activity in hepatocytes, resulting in reduced levels of N-acetyl glutamate (NAG) and therefore a reduced activity of the initiating enzyme of the urea cycle, carbamoyl phosphate synthase (CPS) (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">All these factors can contribute to impairing the ability of the graft to eliminate the excessive ammonia accumulated. In these patients, hyperammonemia is not usually very high, but it can sometimes be a major complication as it induces cerebral edema and leads to neurological symptoms that can leave sequelae. Measures against cerebral edema and dialysis may be necessary treatments at this stage. Ammonia levels should be measured routinely after liver transplantation, and treatment should be started as soon as possible. Although the posttransplantation hyperammonemia episode can hardly be avoided, its duration and intensity could be minimized contributing to actívate the urea cycle in the newly transplanted liver. Patients could benefit from the intake of arginine and carglumic acid (currently commercialized as Carbaglu®), a structural analog of NAG that can bind to and activate the CPS enzyme.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">5,6</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0025" class="elsevierStylePara elsevierViewall">There is no conflict of interest at work.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Case report" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Discussion" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 828 "Ancho" => 1520 "Tamanyo" => 88904 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Urea cycle.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MARS treatment for a patient presenting with acquired hepatic glutamine synthetase deficiency after orthotopic liver transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Chiu" 1 => "S. Tam" 2 => "W.Y. Au" 3 => "S.C. Chan" 4 => "C.L. Liu" 5 => "S.T. Fan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/lt.20363" "Revista" => array:6 [ "tituloSerie" => "Liver Transpl" "fecha" => "2005" "volumen" => "11" "paginaInicial" => "353" "paginaFinal" => "355" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15719403" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0040" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic glutamine synthetase deficiency in fatal hyperammonemia after lung transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Tuchman" 1 => "G.R. Lichtenstein" 2 => "B.S. Rajagopal" 3 => "M.T. McCann" 4 => "E.E. Furth" 5 => "J. Bavaria" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ann Internal Med" "fecha" => "1997" "volumen" => "127" "paginaInicial" => "446" "paginaFinal" => "449" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0045" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver graft preconditioning, preservation and reconditioning" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N. Gilbo" 1 => "G. Catalano" 2 => "M. Salizzoni" 3 => "R. Romagno" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.dld.2016.06.031" "Revista" => array:6 [ "tituloSerie" => "Dig Liver Dis" "fecha" => "2016" "volumen" => "48" "paginaInicial" => "1265" "paginaFinal" => "1274" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27448845" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0050" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel approaches to preventing ischemia–reperfusion injury during liver transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.Z. Akhtar" 1 => "T. Henderson" 2 => "A. Sutherland" 3 => "T. Vogel" 4 => "P.J. Friend" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Transpl Proc" "fecha" => "2013" "volumen" => "45" "paginaInicial" => "2083" "paginaFinal" => "2092" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0055" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Valayannopoulos" 1 => "J. Baruteau" 2 => "M.B. Delgado" 3 => "A. Cano" 4 => "M.L. Couce" 5 => "M. Del Toro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s13023-016-0406-2" "Revista" => array:5 [ "tituloSerie" => "Orphanet J Rare Dis" "fecha" => "2016" "volumen" => "11" "paginaInicial" => "32" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27030250" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0060" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyperammonemia syndrome after lung transplantation: a single center experience" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Chen" 1 => "K.B. Bain" 2 => "J.A. Iuppa" 3 => "R.D. Yusen" 4 => "D.E. Byers" 5 => "G.A. Patterson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/TP.0000000000000868" "Revista" => array:6 [ "tituloSerie" => "Transplantation" "fecha" => "2016" "volumen" => "100" "paginaInicial" => "678" "paginaFinal" => "684" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26335916" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/25300180/0000006700000002/v1_202004190644/S2530018020300147/v1_202004190644/en/main.assets" "Apartado" => array:4 [ "identificador" => "64494" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/25300180/0000006700000002/v1_202004190644/S2530018020300147/v1_202004190644/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018020300147?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 0 | 7 |
| 2024 October | 44 | 0 | 44 |
| 2024 September | 56 | 1 | 57 |
| 2024 August | 62 | 4 | 66 |
| 2024 July | 54 | 5 | 59 |
| 2024 June | 44 | 1 | 45 |
| 2024 May | 51 | 5 | 56 |
| 2024 April | 70 | 10 | 80 |
| 2024 March | 33 | 6 | 39 |
| 2024 February | 30 | 5 | 35 |
| 2024 January | 49 | 5 | 54 |
| 2023 December | 32 | 5 | 37 |
| 2023 November | 30 | 1 | 31 |
| 2023 October | 25 | 3 | 28 |
| 2023 September | 19 | 1 | 20 |
| 2023 August | 14 | 0 | 14 |
| 2023 July | 9 | 1 | 10 |
| 2023 June | 9 | 1 | 10 |
| 2023 May | 8 | 0 | 8 |
| 2023 April | 15 | 0 | 15 |
| 2023 March | 23 | 3 | 26 |
| 2023 February | 15 | 2 | 17 |
| 2023 January | 17 | 1 | 18 |
| 2022 December | 23 | 3 | 26 |
| 2022 November | 16 | 6 | 22 |
| 2022 October | 12 | 6 | 18 |
| 2022 September | 12 | 7 | 19 |
| 2022 August | 12 | 4 | 16 |
| 2022 July | 13 | 6 | 19 |
| 2022 June | 16 | 6 | 22 |
| 2022 May | 15 | 4 | 19 |
| 2022 April | 8 | 9 | 17 |
| 2022 March | 10 | 4 | 14 |
| 2022 February | 10 | 6 | 16 |
| 2022 January | 18 | 6 | 24 |
| 2021 December | 14 | 7 | 21 |
| 2021 November | 11 | 8 | 19 |
| 2021 October | 25 | 7 | 32 |
| 2021 September | 14 | 9 | 23 |
| 2021 August | 17 | 7 | 24 |
| 2021 July | 10 | 9 | 19 |
| 2021 June | 9 | 6 | 15 |
| 2021 May | 21 | 5 | 26 |
| 2021 April | 40 | 9 | 49 |
| 2021 March | 17 | 5 | 22 |
| 2021 February | 10 | 9 | 19 |
| 2021 January | 8 | 5 | 13 |
| 2020 December | 11 | 5 | 16 |
| 2020 November | 13 | 4 | 17 |
| 2020 October | 11 | 2 | 13 |
| 2020 September | 9 | 4 | 13 |
| 2020 August | 7 | 5 | 12 |
| 2020 April | 3 | 0 | 3 |
Show all
