metricas
covid
Buscar en
Neurología (English Edition)
Toda la web
Inicio Neurología (English Edition) Cannabinoids in epilepsy: clinical efficacy and pharmacological considerations
Journal Information

Statistics

Follow this link to access the full text of the article

Review article
Cannabinoids in epilepsy: clinical efficacy and pharmacological considerations
Cannabinoides en epilepsia: eficacia clínica y aspectos farmacológicos
C. Espinosa-Jovela,b,
Corresponding author
camiloespinosajovel@gmail.com

Corresponding author.
a Programa de Epilepsia, Servicio de Neurología, Hospital Occidente de Kennedy, Bogotá, Colombia
b Posgrado de Neurología, Universidad de La Sabana, Chía, Colombia
Read
4120
Times
was read the article
838
Total PDF
3282
Total HTML
Share statistics
 array:25 [
  "pii" => "S2173580821001826"
  "issn" => "21735808"
  "doi" => "10.1016/j.nrleng.2020.02.012"
  "estado" => "S300"
  "fechaPublicacion" => "2023-01-01"
  "aid" => "1389"
  "copyright" => "Sociedad Española de Neurología"
  "copyrightAnyo" => "2020"
  "documento" => "article"
  "crossmark" => 1
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "rev"
  "cita" => "Neurologia. 2023;38:47-53"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "Traduccion" => array:1 [
    "es" => array:20 [
      "pii" => "S0213485320300402"
      "issn" => "02134853"
      "doi" => "10.1016/j.nrl.2020.02.005"
      "estado" => "S300"
      "fechaPublicacion" => "2023-01-01"
      "aid" => "1389"
      "copyright" => "Sociedad Española de Neurología"
      "documento" => "article"
      "crossmark" => 1
      "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
      "subdocumento" => "rev"
      "cita" => "Neurologia. 2023;38:49-55"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:1 [
        "total" => 0
      ]
      "es" => array:13 [
        "idiomaDefecto" => true
        "cabecera" => "<span class="elsevierStyleTextfn">Revisi&#243;n</span>"
        "titulo" => "Cannabinoides en epilepsia&#58; eficacia cl&#237;nica y aspectos farmacol&#243;gicos"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "49"
            "paginaFinal" => "55"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Cannabinoids in epilepsy&#58; Clinical efficacy and pharmacological considerations"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "resumenGrafico" => array:2 [
          "original" => 0
          "multimedia" => array:7 [
            "identificador" => "fig0005"
            "etiqueta" => "Figura 1"
            "tipo" => "MULTIMEDIAFIGURA"
            "mostrarFloat" => true
            "mostrarDisplay" => false
            "figura" => array:1 [
              0 => array:4 [
                "imagen" => "gr1.jpeg"
                "Alto" => 1466
                "Ancho" => 2244
                "Tamanyo" => 202544
              ]
            ]
            "descripcion" => array:1 [
              "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Porcentaje de reducci&#243;n media de frecuencia de crisis en los 3 ensayos cl&#237;nicos que evaluaron la eficacia del CBD como terapia coadyuvante en pacientes con s&#237;ndrome de Dravet y s&#237;ndrome de Lennox-Gastaut&#46; Para los pacientes con s&#237;ndrome de Dravet&#44; la frecuencia de crisis se refiere a las crisis convulsivas&#46; Para los pacientes con s&#237;ndrome de Lennox-Gastaut&#44; la frecuencia de crisis se refiere a las crisis de ca&#237;da&#46; Los valores de p se refieren a las comparaciones entre cada grupo de CDB y el grupo de placebo correspondiente&#46; Para m&#225;s informaci&#243;n&#44; revisar las referencias 35-37&#46; Adaptada de&#58; Perucca<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a>&#46;</p>"
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "C&#46; Espinosa-Jovel"
            "autores" => array:1 [
              0 => array:2 [
                "nombre" => "C&#46;"
                "apellidos" => "Espinosa-Jovel"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "S2173580821001826"
          "doi" => "10.1016/j.nrleng.2020.02.012"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => true
            "ES2" => true
            "LATM" => true
          ]
          "gratuito" => true
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580821001826?idApp=UINPBA00004N"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485320300402?idApp=UINPBA00004N"
      "url" => "/02134853/0000003800000001/v1_202212231625/S0213485320300402/v1_202212231625/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:20 [
    "pii" => "S2173580822001869"
    "issn" => "21735808"
    "doi" => "10.1016/j.nrleng.2022.02.005"
    "estado" => "S300"
    "fechaPublicacion" => "2023-01-01"
    "aid" => "1722"
    "copyright" => "Sociedad Espa&#241;ola de Neurolog&#237;a"
    "documento" => "simple-article"
    "crossmark" => 1
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "cor"
    "cita" => "Neurologia. 2023;38:54-5"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>"
      "titulo" => "Multiple cranial neuropathy secondary to neurolymphomatosis as initial presentation of lymphoma"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "54"
          "paginaFinal" => "55"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Multineuritis craneal por neurolinfomatosis primaria como manifestaci&#243;n inicial de linfoma"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig0005"
          "etiqueta" => "Figure 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 791
              "Ancho" => 805
              "Tamanyo" => 104479
            ]
          ]
          "detalles" => array:1 [
            0 => array:3 [
              "identificador" => "at0005"
              "detalle" => "Figure "
              "rol" => "short"
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Abdomen axial CT scan with intravenous contrast&#46; Both kidneys present hypodense&#44; poorly defined&#44; infiltrative masses mainly affecting the renal medulla&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "A&#46;M&#46; Diezma-Mart&#237;n, M&#46;I&#46; Morales-Casado, M&#46; de la Torre de la Paz, R&#46; Almansa-Castillo"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "A&#46;M&#46;"
              "apellidos" => "Diezma-Mart&#237;n"
            ]
            1 => array:2 [
              "nombre" => "M&#46;I&#46;"
              "apellidos" => "Morales-Casado"
            ]
            2 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "de la Torre de la Paz"
            ]
            3 => array:2 [
              "nombre" => "R&#46;"
              "apellidos" => "Almansa-Castillo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0213485322000172"
        "doi" => "10.1016/j.nrl.2022.02.002"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485322000172?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580822001869?idApp=UINPBA00004N"
    "url" => "/21735808/0000003800000001/v1_202301170615/S2173580822001869/v1_202301170615/en/main.assets"
  ]
  "itemAnterior" => array:20 [
    "pii" => "S2173580822001006"
    "issn" => "21735808"
    "doi" => "10.1016/j.nrleng.2020.03.005"
    "estado" => "S300"
    "fechaPublicacion" => "2023-01-01"
    "aid" => "1430"
    "copyright" => "Sociedad Espa&#241;ola de Neurolog&#237;a"
    "documento" => "article"
    "crossmark" => 1
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "rev"
    "cita" => "Neurologia. 2023;38:41-6"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
      "titulo" => "Do patients diagnosed with a neurological disease present increased risk of suicide&#63;"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "41"
          "paginaFinal" => "46"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "&#191;Existe mayor riesgo de suicidio en pacientes diagnosticados de una enfermedad neurol&#243;gica&#63;"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "M&#46; Alejos, J&#46; V&#225;zquez-Bourgon, M&#46; Santurt&#250;n, J&#46; Riancho, A&#46; Santurt&#250;n"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Alejos"
            ]
            1 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "V&#225;zquez-Bourgon"
            ]
            2 => array:2 [
              "nombre" => "M&#46;"
              "apellidos" => "Santurt&#250;n"
            ]
            3 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "Riancho"
            ]
            4 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "Santurt&#250;n"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "S0213485320301298"
        "doi" => "10.1016/j.nrl.2020.03.003"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485320301298?idApp=UINPBA00004N"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580822001006?idApp=UINPBA00004N"
    "url" => "/21735808/0000003800000001/v1_202301170615/S2173580822001006/v1_202301170615/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
    "titulo" => "Cannabinoids in epilepsy&#58; clinical efficacy and pharmacological considerations"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "47"
        "paginaFinal" => "53"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "C&#46; Espinosa-Jovel"
        "autores" => array:1 [
          0 => array:4 [
            "nombre" => "C&#46;"
            "apellidos" => "Espinosa-Jovel"
            "email" => array:1 [
              0 => "camiloespinosajovel@gmail.com"
            ]
            "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">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:2 [
          0 => array:3 [
            "entidad" => "Programa de Epilepsia&#44; Servicio de Neurolog&#237;a&#44; Hospital Occidente de Kennedy&#44; Bogot&#225;&#44; Colombia"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Posgrado de Neurolog&#237;a&#44; Universidad de La Sabana&#44; Ch&#237;a&#44; Colombia"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Cannabinoides en epilepsia&#58; eficacia cl&#237;nica y aspectos farmacol&#243;gicos"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:9 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from&#58; Perucca&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1623
            "Ancho" => 2507
            "Tamanyo" => 237349
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mean reduction in seizure frequency in the 3 clinical trials evaluating the efficacy of CBD as an adjuvant therapy in patients with Dravet syndrome and Lennox-Gastaut syndrome&#46; For Dravet syndrome&#44; seizure frequency refers to convulsive seizures&#46; For Lennox-Gastaut syndrome&#44; seizure frequency refers to drop attacks&#46; <span class="elsevierStyleItalic">P</span>-values refer to comparisons between the CBD group and the placebo group in each trial&#46; References <a class="elsevierStyleCrossRefs" href="#bib0175">35&#8211;37</a> provide further information on these results&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The lack of satisfactory results in the treatment of some neurological diseases has led to a search for more effective medications with new action mechanisms&#46; Within the search for new drugs&#44; cannabis-based products have emerged as a safe and effective treatment alternative&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Today&#44; cannabinoids are considered a complementary tool for the symptomatic management of various chronic neurological diseases when other first-line therapies have failed&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Current evidence supports the use of cannabis-based products to treat refractory epilepsy&#59; chronic neuropathic pain&#59; spasticity and bladder dysfunction associated with multiple sclerosis&#59; movement disorders including tremor&#44; dystonia&#44; and Tourette syndrome&#59; headache&#59; and some sleep disorders associated with neurological diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> For decades&#44; the prescription of cannabinoids for therapeutic purposes has been subject to restrictions and controls under specific regulatory frameworks&#44; which has limited the development&#44; clinical research&#44; and commercialisation of cannabinoids for medicinal use&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; recent years have seen significant advances worldwide in favour of the safe use and responsible prescription of medicinal cannabis for various clinical conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Furthermore&#44; new regulations have allowed for the exponential growth of clinical research into the use of cannabinoids for several neurological diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> The objective of this article is to examine epidemiological aspects of the use of cannabis-based products to treat epilepsy&#44; with an emphasis on their main action mechanisms&#44; indications&#44; clinical efficacy&#44; and safety&#46; To that end&#44; we conducted a narrative review of the relevant literature on the use of cannabinoids to treat epilepsy&#44; based on a search of the PubMed&#44; EMBASE&#44; and Google Scholar databases&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Epidemiological aspects</span><p id="par0010" class="elsevierStylePara elsevierViewall">Epilepsy is one of the most frequent neurological diseases&#44; affecting approximately 70 million people worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> While epilepsy is a global disease&#44; it is unequally distributed&#44; with almost 80&#37; of affected individuals living in populations with limited economic resources&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> Epilepsy is treatable&#44; with high rates of treatment response&#58; approximately 70&#37; of patients control their disease with antiepileptic drugs and live normal lives&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> More than 25 drugs are currently available for seizure control&#59; however&#44; despite the multiple therapeutic alternatives and the development of new drugs&#44; 25&#37;-35&#37; of patients do not respond to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> This situation is known as refractory epilepsy&#44; and constitutes a frequent&#44; chronic&#44; and economically costly condition requiring integrated multidisciplinary management&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Refractory epilepsy predisposes to numerous neuropsychiatric comorbidities and has a considerable impact on patients&#8217; quality of life and increases the rates of morbidity and mortality associated with the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> Advances in the development of drugs with novel action mechanisms have been insufficient to significantly reduce the percentage of patients with refractory epilepsy&#59; this has been demonstrated in different prospective cohorts evaluating treatment response over periods longer than 30 years&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> These studies have found that up to 36&#37; of patients continue to present seizures despite treatment with several appropriately selected drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The lack of satisfactory clinical outcomes has led to a search for more effective treatments with different action mechanisms than those of conventional treatments&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">In recent years&#44; there has been growing interest in the treatment of epilepsy with medicinal cannabis&#46; Cannabis plants contain more than 100 terpenophenolic compounds&#44; termed cannabinoids&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The 2 most abundant compounds are delta-9-tetrahydrocannabinol &#40;&#916;9-THC&#41; and cannabidiol &#40;CBD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Various preclinical models of epilepsy have suggested that cannabinoids act on systems other than the endocannabinoid system&#44; opening the door to potential new treatment strategies and novel action mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Several recent case reports have described a significant improvement in seizure control with the use of different cannabis-based products&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Randomised controlled trials have begun to confirm the considerable expectations that have arisen from these isolated case reports&#46; To date&#44; 3 clinical trials have evaluated the efficacy of CBD for controlling certain epileptic syndromes &#40;Dravet syndrome and Lennox-Gastaut syndrome&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Although the results are promising&#44; several studies have demonstrated that CBD presents complex pharmacokinetics&#44; variable bioavailability&#44; and a high rate of drug-drug interactions&#59; as a result&#44; researchers have searched for different therapeutic and pharmacological alternatives&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> For example&#44; some studies have used CBD-enriched cannabis extracts&#44; which usually have a CBD&#58;THC ratio of 20&#58;1&#59; this approach is justified by various preclinical and pharmacological studies&#44; which suggest that the entourage effect of all the plant&#8217;s components results in greater efficacy than that of isolated chemical compounds&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In some countries&#44; including Israel&#44; studies into the efficacy of these products for controlling refractory epilepsy have found that more than 50&#37; of patients achieve a significant improvement in seizure frequency&#59; furthermore&#44; the authors observed subjective improvements in behaviour&#44; alertness&#44; communication&#44; and some motor skills&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Action mechanism and pharmacological considerations</span><p id="par0020" class="elsevierStylePara elsevierViewall">The action mechanism&#44; pharmacokinetics&#44; and pharmacodynamics of cannabinoids are complex&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> Cannabis plants contain more than 100 phytocannabinoids and terpenes that act through complex molecular pathways and signalling networks&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The most abundant and most studied compounds in different cannabis plants are &#916;9-THC and CBD&#46; These molecules act through G protein&#8211;coupled receptors&#44; which belong to the endocannabinoid system and are classified as CB1 &#40;mainly expressed by neurons in the central and peripheral nervous systems&#41; and CB2 &#40;mainly expressed by immune system cells&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> CB1 receptors reduce neuronal excitability and the release of neurotransmitters by modulating the opening of potassium channels and blocking calcium channels&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;16&#44;17</span></a> CB2 receptors are involved in immune modulation&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> &#916;9-THC is a partial CB1&#47;CB2 receptor agonist and has a potent anti-inflammatory effect&#59; however&#44; as it is responsible for the majority of the plant&#8217;s psychotropic&#44; cognitive&#44; and behavioural effects&#44; little effort has been made to develop THC as an antiepileptic drug&#46; Furthermore&#44; some preclinical studies have found THC to have proconvulsant properties&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Most studies into epilepsy have focused on CBD and its analogue&#44; cannabidivarin&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Unlike &#916;9-THC&#44; CBD has very low affinity for CB1 and CB2 receptors &#40;which would explain its reduced psychotropic activity&#41;&#59; as a result&#44; it has been suggested that the compound&#8217;s antiepileptic activity does not involve the endocannabinoid system&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> While its exact action mechanism in patients with epilepsy is currently unknown&#44; several hypotheses have been suggested&#46; For instance&#44; it modulates the ENT transporter&#44; the GPR55 receptor&#44; and the TRPM8 channel&#44; which are involved in neuronal hyperexcitability&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> It also modulates the activation of the 5HT1a serotonergic receptor&#44; some glycine receptors&#44; and the TRPA1 channel&#44; which contribute to the regulation of intracellular calcium concentrations&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Furthermore&#44; CBD is a potent inhibitor of certain hepatic enzymes &#40;CYP3A4&#44; CYP2C9&#44; and CYP2C19&#41;&#59; it consequently inhibits the metabolism of some antiepileptic drugs using the same enzyme system&#44; potentiating their antiepileptic properties&#59; this is the case for clobazam&#44; topiramate&#44; zonisamide&#44; and eslicarbazepine&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The oral bioavailability of CBD is very low &#40;less than 10&#37;&#41;&#44; which is partially explained by its high first-pass metabolism in the gut and liver&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The elimination half-life of CBD ranges from 18 to 32&#160;hours&#44; enabling administration once or twice per day&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;19</span></a> Some studies suggest that the combined effects of all the plant&#8217;s components are associated with better efficacy than the isolated compounds &#40;CBD and &#916;9-THC&#41;&#46; This phenomenon is known as the entourage effect&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> This indicates that the clinical effects of cannabis are secondary to complex interactions between different cannabinoids&#44; rather than the action of an isolated compound&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;21</span></a> This hypothesis is supported by several studies that have demonstrated that CBD potentiates some of the beneficial properties of &#916;9-THC and reduces its psychotropic effects&#44; improving tolerability&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;22</span></a> CBD seemingly has the capacity to counteract some of the functional effects of CB1 receptor activation in the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> This may explain why users of cannabis with a high CBD&#58;THC ratio experience few psychotropic effects compared to those who consume cannabis with a lower proportion of CBD&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Clinical efficacy</span><p id="par0025" class="elsevierStylePara elsevierViewall">Evidence from 34 studies of 6 animal species suggests that &#916;9-THC acts as an anticonvulsant in 61&#37; of cases&#44; a proconvulsant in 2&#46;9&#37;&#44; presents a mixed response in 2&#46;9&#37;&#44; and has no significant effect in 32&#46;4&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;23</span></a> CBD and its homologue&#44; cannabidivarin&#44; are anticonvulsant in 80&#46;5&#37; of cases and have no significant effect in 19&#46;5&#37; of cases&#46; Unlike &#916;9-THC&#44; CBD and cannabidivarin have not been shown to present proconvulsant properties in any preclinical trial&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;23</span></a> Based on these studies of animal models&#44; pure CBD and CBD-enriched cannabis extracts have begun to be used to treat epilepsy in human patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Clinical efficacy of cannabidiol-enriched cannabis extracts</span><p id="par0030" class="elsevierStylePara elsevierViewall">Published cases of the use of CBD-enriched cannabis extracts report diverging results &#40;both anticonvulsant and proconvulsant effects&#41;&#59; however&#44; most authors describe subjective improvements in seizure frequency&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;28</span></a> One of the best-known cases&#44; which generated considerable media coverage&#44; was that of Charlotte Figi&#44; an American child with Dravet syndrome and refractory epilepsy who presented a significant improvement in seizure control after using a CBD-enriched cannabis extract&#46; Several surveys have also been conducted to collect data from the family members and caregivers of patients with epilepsy&#46; One of the most important of these studies was published in 2015 by Hussain et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The survey was distributed to the parents of children aged 3-10 years who had epilepsy &#40;infantile spasms and Lennox&#8211;Gastaut syndrome&#41; and were using a CBD-enriched cannabis extract&#46; Eighty-five percent of respondents reported a reduction in seizure frequency&#44; and 14&#37; reported complete seizure freedom&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Mean treatment duration was 6&#46;8 months&#44; and the approximate CBD dose was 4&#46;3&#160;mg&#47;kg&#47;day&#46; Many participants also reported improvements in sleep&#44; alertness&#44; and mood&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> In a recent survey conducted in Australia&#44; 137 of 976 respondents were using or had used cannabis products to treat epilepsy&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> These products were effective for seizure control in 71&#37; of children and 89&#46;5&#37; of adults&#59; furthermore&#44; nearly half of respondents reported a reduction in the concomitant use of antiepileptic drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In that study&#44; only 6&#46;5&#37; of respondents reported that they used cannabis following recommendation by a physician&#44; and the majority of the products used were obtained from illegal suppliers and no clear information on their composition was available&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In another recent study conducted in Mexico&#44; a survey was distributed to 53 parents of paediatric patients with epilepsy aged between 9 months and 18 years&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The majority of patients had Lennox&#8211;Gastaut syndrome or unspecified refractory epilepsy&#46; Eighty-one percent of parents reported a reduction in seizure frequency with CBD-enriched cannabis extracts&#44; with 16&#37; reporting complete seizure freedom&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The main limitation of these studies is the variability in the types of epilepsy analysed and differences in the chemical compounds used&#44; dosage&#44; route of administration&#44; and manufacture&#46; Furthermore&#44; home-made cannabis extract products are relatively easy to procure in some countries&#44; resulting in considerable variation in quality control and the chemical consistency of the products&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Given these limitations&#44; it is unsurprising that many preparations are not subject to appropriate quality validation and that the content of individual cannabinoids in some marketed products differs considerably from the values printed on their label&#59; some may even contain potentially harmful contaminants&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The United States Food and Drug Administration evaluated 18 cannabis-based products that are freely marketed for controlling epilepsy&#44; finding that 8 contained no CBD&#44; 9 contained less than 1&#37; CBD&#44; and one contained 2&#46;6&#37; CBD&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> A recent Australian study reported similar results&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> That study evaluated the composition of cannabis extracts used by 65 patients with refractory epilepsy and found that&#44; contrary to the expectations of the patients&#8217; families&#44; most of the samples studied contained low concentrations of CBD&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Therefore&#44; it is important to use standardised products that comply with regulatory&#44; healthcare&#44; and legal controls in each country&#46; In Israel&#44; for example&#44; a CBD-enriched cannabis extract is marketed with CBD&#58;THC ratios of 2&#58;1&#44; 5&#58;1&#44; and 20&#58;1&#44; with the latter being used most frequently&#46; This product is standardised and meets local legal and healthcare requirements&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> A recent study evaluated the efficacy of this product for controlling epilepsy&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The authors assessed 74 patients with refractory epilepsy using the CBD-enriched cannabis extract with a CBD&#58;THC ratio of 20&#58;1&#46; The dose of THC did not exceed 0&#46;5&#160;mg&#47;kg&#47;day&#44; and the CBD dose ranged from 1 to 20&#160;mg&#47;kg&#47;day&#59; however&#44; 81&#37; of patients received doses below 10&#160;mg&#47;kg&#47;day&#44; which was attributed to the fact that the majority of patients held the product under the tongue for several minutes&#44; improving bioavailability and reducing first-pass metabolism&#46; Approximately half of patients&#8217; parents reported a &#62; 50&#37; reduction in seizure frequency&#46; Improvements were also observed in behaviour&#44; alertness&#44; language&#44; communication&#44; motor skills&#44; and sleep&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Clinical efficacy of pure cannabidiol</span><p id="par0040" class="elsevierStylePara elsevierViewall">Three randomised controlled clinical trials have evaluated the use of pure CBD&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> One of these studies was conducted in patients with Dravet syndrome&#44; and the other 2 included patients with Lennox-Gastaut syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;37</span></a> The former study included patients aged between 2&#46;3 and 18 years&#59; 43&#37; of participants achieved a &#62; 50&#37; reduction in seizure frequency and 5&#37; achieved complete seizure freedom&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> The study of patients with Lennox-Gastaut syndrome included patients aged between 2 and 55 years&#44; with 46&#37; achieving a &#62; 50&#37; reduction in seizure frequency and 6&#37; achieving seizure freedom&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> summarises the main findings of these studies&#46; One of the main limitations of the study of patients with Dravet syndrome is the fact that up to 66&#37; of patients receiving CBD were also using clobazam<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#59; this correlation may have considerable clinical relevance&#44; in the light of recent evidence indicating that levels of <span class="elsevierStyleItalic">n</span>-desmethylclobazam &#40;the active metabolite of clobazam&#41; can increase by up to 500&#37; after CBD use&#46; Therefore&#44; we are unable to determine whether the improvement in seizure frequency was a result of the direct action of CBD or simply due to the increased plasma levels of coadjuvant drugs&#44; principally clobazam&#44; based on the data reported in these trials&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">It remains to be established whether the efficacy of CBD is independent of the concomitant use of other drugs&#46; Regarding this point&#44; a recently published study demonstrated a new pharmacodynamic mechanism by which CBD and clobazam increase the activation of the GABA receptor&#44; contributing to the anticonvulsant effect of the combination of both drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Another recent study also demonstrated that the therapeutic response to a CBD-enriched cannabis extract was independent of the use of clobazam&#44; and that clobazam contributed significantly to the sedative effects of CBD&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Adverse reactions</span><p id="par0050" class="elsevierStylePara elsevierViewall">Studies into the safety and effectiveness of CBD-enriched cannabis extracts report adverse reactions in 35&#37;-45&#37; of patients<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;29&#8211;31</span></a>&#59; these rates are lower than those reported in clinical trials of pure CBD &#40;adverse reactions in up to 79&#37; of patients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;37</span></a> The majority of adverse effects are mild and transient&#44; and are largely explained by drug-drug interactions&#44; particularly with clobazam&#44; topiramate&#44; zonisamide&#44; and eslicarbazepine&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the most frequent adverse reactions reported in the literature&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusion</span><p id="par0055" class="elsevierStylePara elsevierViewall">Cannabinoids are considered a complementary tool for the symptomatic management of various neurological diseases when other first-line therapies have failed&#46; Two therapeutic options are available to treat refractory epilepsy&#58; pure CBD and CBD-enriched cannabis extracts&#46; While both products contain the same active ingredient&#44; it is not appropriate to extrapolate the results of clinical trials of pure CBD to CBD-enriched cannabis extracts&#46; The 2 products are functionally distinct&#44; with each presenting specific pharmacokinetic properties&#46; CBD-enriched cannabis extracts constitute a model of botanical synergy in which the clinical effect is thought to be the result of complex interactions between all the components of the plant&#44; rather than an isolated chemical product&#44; as would be the case with pure CBD&#46; It should be noted that this therapeutic difference is hypothetical&#58; the exact action mechanism is not known in either case&#44; although the majority of preclinical models demonstrate anticonvulsant properties&#46; Furthermore&#44; the current evidence on CBD-enriched cannabis extracts is insufficient for therapeutic decision-making&#59; there is a need for controlled clinical trials to confirm the clinical efficacy and safety of these products&#46; Nonetheless&#44; the case reports&#44; targeted surveys&#44; and open-label trials published to date indicate that they may represent a safe&#44; effective treatment for refractory epilepsy&#46; Unlike CBD-enriched cannabis extracts&#44; robust scientific evidence is available for the use of pure CBD&#58; the results of 3 randomised controlled clinical trials support its use for the treatment of refractory epilepsy in patients with Dravet syndrome and Lennox-Gastaut syndrome&#46; Many open questions must be addressed in specific studies&#46; For instance&#44; it is yet to be established whether the action mechanism of CBD is independent of drug-drug interactions&#44; particularly with clobazam&#59; we also currently lack information about its long-term safety&#44; especially with regard to brain development and during pregnancy&#46; Despite these questions&#44; cannabinoids constitute a promising alternative for the treatment of patients with refractory epilepsy&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">Dr Camilo Espinosa-Jovel has consulted for the following pharmaceutical companies&#58; BIOPAS Laboratoires&#44; Khiron Life Sciences Corp&#46;&#44; UCB Pharma&#44; and Abbott&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:12 [
        0 => array:3 [
          "identificador" => "xres1833261"
          "titulo" => "Abstract"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Introduction"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Development"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1598054"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres1833260"
          "titulo" => "Resumen"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Introducci&#243;n"
            ]
            1 => array:2 [
              "identificador" => "abst0025"
              "titulo" => "Desarrollo"
            ]
            2 => array:2 [
              "identificador" => "abst0030"
              "titulo" => "Conclusiones"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1598055"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Epidemiological aspects"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Action mechanism and pharmacological considerations"
        ]
        7 => array:3 [
          "identificador" => "sec0020"
          "titulo" => "Clinical efficacy"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Clinical efficacy of cannabidiol-enriched cannabis extracts"
            ]
            1 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Clinical efficacy of pure cannabidiol"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Adverse reactions"
        ]
        9 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conclusion"
        ]
        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflicts of interest"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2019-11-18"
    "fechaAceptado" => "2020-02-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1598054"
          "palabras" => array:6 [
            0 => "Cannabinoids"
            1 => "Cannabis"
            2 => "Marijuana"
            3 => "Cannabidiol"
            4 => "Tetrahydrocannabinol"
            5 => "Epilepsy"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1598055"
          "palabras" => array:6 [
            0 => "Cannabinoides"
            1 => "Cannabis"
            2 => "Marihuana"
            3 => "Cannabidiol"
            4 => "Tetrahidrocannabinol"
            5 => "Epilepsia"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting drug-resistant epilepsy&#46; This lack of satisfactory clinical results has led to the search for more effective treatment alternatives with new mechanisms of action&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Development</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The aim of this study is to examine epidemiological aspects of the use of cannabis-based products for the treatment of epilepsy&#44; with particular emphasis on the main mechanisms of action&#44; indications for use&#44; clinical efficacy&#44; and safety&#46; We conducted a narrative review of articles gathered from the PubMed&#44; EMBASE&#44; and Google Scholar databases and from the reference sections of relevant publications&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">In recent years there has been growing interest in the use of cannabis-based products for the treatment of a wide range of diseases&#44; including epilepsy&#46; The cannabis plant is currently known to contain more than 100 terpenophenolic compounds&#44; known as cannabinoids&#46; The 2 most abundant are delta-9-tetrahydrocannabinol and cannabidiol&#46; Studies of preclinical models of epilepsy have shown that these cannabinoids have anticonvulsant properties&#44; and 100&#37; purified cannabidiol and cannabidiol-enriched cannabis extracts are now being used to treat epilepsy in humans&#46; Several open-label studies and randomised controlled clinical trials have demonstrated the efficacy and safety of these products&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Development"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introducci&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los avances en el desarrollo de medicamentos con mecanismos de acci&#243;n novedosos no han sido suficientes para modificar de manera significativa el porcentaje de pacientes con epilepsia refractaria&#46; Esa falta de resultados cl&#237;nicos satisfactorios nos ha llevado a buscar alternativas terap&#233;uticas m&#225;s eficaces y con mecanismos de acci&#243;n diferentes a los convencionales&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Desarrollo</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este art&#237;culo es profundizar en los aspectos epidemiol&#243;gicos relacionados con el uso de productos a base de cannabis para el tratamiento de la epilepsia&#44; haciendo &#233;nfasis en los principales mecanismos de acci&#243;n&#44; las indicaciones de uso&#44; la eficacia cl&#237;nica y la seguridad&#46; Para lo anterior&#44; se realiz&#243; una revisi&#243;n narrativa mediante la b&#250;squeda de art&#237;culos en PubMed&#44; EMBASE&#44; Google Scholar y a trav&#233;s de la revisi&#243;n exhaustiva de la bibliograf&#237;a relevante&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">En los &#250;ltimos a&#241;os ha crecido el inter&#233;s relacionado con el uso de cannabis medicinal para el tratamiento de diferentes enfermedades&#44; incluyendo la epilepsia&#46; En la actualidad&#44; sabemos que las plantas de cannabis contienen m&#225;s de 100 compuestos terpenofen&#243;licos que se han denominado cannabinoides&#46; Los 2 m&#225;s abundantes son el delta-9-tetrahidrocannabinol y el cannabidiol&#46; Diferentes modelos precl&#237;nicos de epilepsia han demostrado que estos cannabinoides tienen propiedades anticonvulsivas&#44; por ello se ha comenzado a utilizar cannabidiol purificado al 100&#37; y extractos de cannabis enriquecidos con cannabidiol para el tratamiento de la epilepsia en humanos&#46; La eficacia y la seguridad de estos productos han quedado demostradas en diferentes estudios abiertos y ensayos cl&#237;nicos controlados y aleatorizados&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Desarrollo"
          ]
          2 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "multimedia" => array:3 [
      0 => array:9 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from&#58; Perucca&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1623
            "Ancho" => 2507
            "Tamanyo" => 237349
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mean reduction in seizure frequency in the 3 clinical trials evaluating the efficacy of CBD as an adjuvant therapy in patients with Dravet syndrome and Lennox-Gastaut syndrome&#46; For Dravet syndrome&#44; seizure frequency refers to convulsive seizures&#46; For Lennox-Gastaut syndrome&#44; seizure frequency refers to drop attacks&#46; <span class="elsevierStyleItalic">P</span>-values refer to comparisons between the CBD group and the placebo group in each trial&#46; References <a class="elsevierStyleCrossRefs" href="#bib0175">35&#8211;37</a> provide further information on these results&#46;</p>"
        ]
      ]
      1 => array:9 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Chen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of the 4 large prospective cohort studies evaluating treatment response in patients recently diagnosed with epilepsy&#46; Despite numerous advances in the development of new antiepileptic drugs&#44; the percentage of patients with refractory epilepsy has not significantly decreased in recent years&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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"><th 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" scope="col" style="border-bottom: 2px solid black">Assessment period&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Year of analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">No&#46; patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Total &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1982-1997&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1999&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">470&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kwan and Brodie &#40;2000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1982-2001&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2003&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">780&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;4&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohanrah and Brodie &#40;2006&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1982-2006&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2008&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1098&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&#46;4&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brodie et al&#46; &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1982-2012&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1795&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;8&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Percentage of responders in 3 cohorts of patients recently diagnosed with epilepsy&#46;</p>"
        ]
      ]
      2 => array:9 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Brodie and Ben-Menachem<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and Perucca&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0015"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Adverse reactions reported both for pure cannabidiol and for cannabidiol-enriched cannabis extracts&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Drowsiness and fatigue&#44; particularly in patients concomitantly using clobazam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Changes in appetite &#40;increase or decrease&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Changes in body weight &#40;increase or decrease&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gastrointestinal symptoms&#58; nausea&#44; vomiting&#44; diarrhoea&#44; constipation&#44; etc&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irritability and behavioural changes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased transaminase levels and thrombocytopaenia&#44; particularly in patients concomitantly using valproic acid&#46; Most studies report an improvement in transaminase levels after the dose of valproic acid or the cannabis extract is reduced&#46; Isolated cases of hyperammonaemia have been reported&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some studies describe increased seizure frequency&#59; however&#44; most authors consider this change to constitute part of the natural history of the disease&#44; rather than an effect of the product&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The most frequently reported adverse reactions to cannabinoids in patients with epilepsy&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabis and epilepsy&#58; an ancient treatment returns to the fore"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;B&#46; Russo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yebeh.2016.09.040"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsy Behav&#46;"
                        "fecha" => "2017"
                        "volumen" => "70"
                        "paginaInicial" => "292"
                        "paginaFinal" => "297"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27989385"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety&#44; efficacy&#44; and mechanisms of action of cannabinoids in neurological disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46; Friedman"
                            1 => "J&#46;A&#46; French"
                            2 => "M&#46; Maccarrone"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1474-4422(19)30032-8"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet Neurol&#46;"
                        "fecha" => "2019"
                        "volumen" => "18"
                        "paginaInicial" => "504"
                        "paginaFinal" => "512"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30910443"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0261561414000430"
                          "estado" => "S300"
                          "issn" => "02615614"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabis therapeutics and the future of neurology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;B&#46; Russo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Integr Neurosci&#46;"
                        "fecha" => "2018"
                        "volumen" => "18"
                        "paginaInicial" => "51"
                        "itemHostRev" => array:3 [
                          "pii" => "S2468125318303418"
                          "estado" => "S300"
                          "issn" => "24681253"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medical use of cannabis and cannabinoids containing products &#8211; regulations in Europe and North America"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Abuhasira"
                            1 => "L&#46; Shbiro"
                            2 => "Y&#46; Landschaft"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejim.2018.01.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Intern Med&#46;"
                        "fecha" => "2018"
                        "volumen" => "49"
                        "paginaInicial" => "2"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29329891"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Medicinal use of cannabis in the United States&#58; historical perspectives&#44; current trends&#44; and future directions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46;K&#46; Aggarwal"
                            1 => "G&#46;T&#46; Carter"
                            2 => "M&#46;D&#46; Sullivan"
                            3 => "C&#46; ZumBrunnen"
                            4 => "R&#46; Morrill"
                            5 => "J&#46;D&#46; Mayer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5055/jom.2009.0016"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Opioid Manag&#46;"
                        "fecha" => "2009"
                        "volumen" => "5"
                        "paginaInicial" => "153"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19662925"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimation of the burden of active and life-time epilepsy&#58; a meta-analytic approach"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;K&#46; Ngugi"
                            1 => "C&#46; Bottomley"
                            2 => "I&#46; Kleinschmidt"
                            3 => "J&#46;W&#46; Sander"
                            4 => "C&#46;R&#46; Newton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2010"
                        "volumen" => "51"
                        "paginaInicial" => "883"
                        "paginaFinal" => "890"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epilepsy in Colombia&#58; epidemiologic profile and classification of epileptic seizures and syndromes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Velez"
                            1 => "J&#46; Eslava-Cobos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1528-1167.2006.00387.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2006"
                        "volumen" => "47"
                        "paginaInicial" => "193"
                        "paginaFinal" => "201"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16417549"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiological profile of epilepsy in low income populations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Espinosa-Jovel"
                            1 => "R&#46; Toledano"
                            2 => "&#193; Aledo-Serrano"
                            3 => "I&#46; Garc&#237;a-Morales"
                            4 => "A&#46; Gil-Nagel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.seizure.2018.02.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Seizure&#46;"
                        "fecha" => "2018"
                        "volumen" => "56"
                        "paginaInicial" => "67"
                        "paginaFinal" => "72"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29453113"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug-resistant epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "P&#46; Kwan"
                            1 => "S&#46;C&#46; Schachter"
                            2 => "M&#46;J&#46; Brodie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1004418"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "919"
                        "paginaFinal" => "926"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21899452"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Farmacorresistencia en epilepsia&#46; Conceptos cl&#237;nicos y neurobiol&#243;gicos"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;A&#46; Espinosa-Jovel"
                            1 => "F&#46;E&#46; Sobrino Mej&#237;a"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rev Neurol&#46;"
                        "fecha" => "2015"
                        "volumen" => "61"
                        "paginaInicial" => "159"
                        "paginaFinal" => "166"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Z&#46; Chen"
                            1 => "M&#46;J&#46; Brodie"
                            2 => "D&#46; Liew"
                            3 => "P&#46; Kwan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamaneurol.2017.3949"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Neurol&#46;"
                        "fecha" => "2018"
                        "volumen" => "75"
                        "paginaInicial" => "279"
                        "paginaFinal" => "286"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29279892"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The case for medical marijuana in epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; Maa"
                            1 => "P&#46; Figi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/epi.12610"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2014"
                        "volumen" => "55"
                        "paginaInicial" => "783"
                        "paginaFinal" => "786"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24854149"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabinoids and epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "E&#46;C&#46; Rosenberg"
                            1 => "R&#46;W&#46; Tsien"
                            2 => "B&#46; Whalley"
                            3 => "O&#46; Devinsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s13311-015-0375-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurotherapeutics&#46;"
                        "fecha" => "2015"
                        "volumen" => "12"
                        "paginaInicial" => "747"
                        "paginaFinal" => "768"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26282273"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabinoids for epilepsy&#58; what do we know and where do we go&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;J&#46; Brodie"
                            1 => "E&#46; Ben-Menachem"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/epi.13973"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2018"
                        "volumen" => "59"
                        "paginaInicial" => "291"
                        "paginaFinal" => "296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29214639"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CBD-enriched medical cannabis for intractable pediatric epilepsy&#58; The current Israeli experience"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Tzadok"
                            1 => "S&#46; Uliel-Siboni"
                            2 => "I&#46; Linder"
                            3 => "U&#46; Kramer"
                            4 => "O&#46; Epstein"
                            5 => "S&#46; Menascu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.seizure.2016.01.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Seizure&#46;"
                        "fecha" => "2016"
                        "volumen" => "35"
                        "paginaInicial" => "41"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26800377"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phytocannabinoids and epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46;G&#46; Dos Santos"
                            1 => "J&#46;E&#46; Hallak"
                            2 => "J&#46;P&#46; Leite"
                            3 => "A&#46;W&#46; Zuardi"
                            4 => "J&#46;A&#46; Crippa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jcpt.12238"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Pharm Ther&#46;"
                        "fecha" => "2015"
                        "volumen" => "40"
                        "paginaInicial" => "125"
                        "paginaFinal" => "143"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25545040"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabinoids"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46; Howard"
                            1 => "R&#46; Twycross"
                            2 => "J&#46; Shuster"
                            3 => "M&#46; Mihalyo"
                            4 => "A&#46; Wilcock"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Pain Sympt Manage&#46;"
                        "fecha" => "2013"
                        "volumen" => "46"
                        "paginaInicial" => "142"
                        "paginaFinal" => "148"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids&#58; delta9-tetrahydrocannabinol&#44; cannabidiol and delta9-tetrahydrocannabivarin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;G&#46; Pertwee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Pharmacol&#46;"
                        "fecha" => "2008"
                        "volumen" => "153"
                        "paginaInicial" => "199"
                        "paginaFinal" => "215"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabidiol&#58; pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Devinsky"
                            1 => "M&#46;R&#46; Cilio"
                            2 => "H&#46; Cross"
                            3 => "J&#46; Fernandez-Ruiz"
                            4 => "J&#46; French"
                            5 => "C&#46; Hill"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/epi.12631"
                      "Revista" => array:7 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2014"
                        "volumen" => "55"
                        "paginaInicial" => "791"
                        "paginaFinal" => "802"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24854329"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S016882781300754X"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exogenous cannabinoids as substrates&#44; inhibitors&#44; and inducers of human drug metabolising enzymes&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;M&#46; Stout"
                            1 => "N&#46;M&#46; Cimino"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/03602532.2013.849268"
                      "Revista" => array:6 [
                        "tituloSerie" => "Drug Metab Rev&#46;"
                        "fecha" => "2014"
                        "volumen" => "46"
                        "paginaInicial" => "86"
                        "paginaFinal" => "95"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24160757"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Taming THC&#58; potential cannabis synergy and phytocannabinoid-terpenoid entourage effects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;B&#46; Russo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1476-5381.2011.01238.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Br J Pharmacol&#46;"
                        "fecha" => "2011"
                        "volumen" => "163"
                        "paginaInicial" => "1344"
                        "paginaFinal" => "1364"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21749363"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0213005X17303294"
                          "estado" => "S300"
                          "issn" => "0213005X"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabidiol inhibits THC elicited paranoid symptoms and hippocampal-dependent memory impairment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Englund"
                            1 => "P&#46;D&#46; Morrison"
                            2 => "J&#46; Nottage"
                            3 => "D&#46; Hague"
                            4 => "F&#46; Kane"
                            5 => "S&#46; Bonaccorso"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/0269881112460109"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Psychopharmacol&#46;"
                        "fecha" => "2013"
                        "volumen" => "27"
                        "paginaInicial" => "19"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23042808"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0261561413002380"
                          "estado" => "S300"
                          "issn" => "02615614"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabinoids in the treatment of epilepsy&#58; hard evidence at last&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46; Perucca"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.14581/jer.17012"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Epilepsy Res&#46;"
                        "fecha" => "2017"
                        "volumen" => "7"
                        "paginaInicial" => "61"
                        "paginaFinal" => "76"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29344464"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Seizure exacerbation in two patients with focal epilepsy following marijuana cessation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Hegde"
                            1 => "C&#46; Santos-Sanchez"
                            2 => "C&#46;P&#46; Hess"
                            3 => "A&#46;A&#46; Kabir"
                            4 => "P&#46;A&#46; Garcia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yebeh.2012.09.024"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsy Behav&#46;"
                        "fecha" => "2012"
                        "volumen" => "25"
                        "paginaInicial" => "563"
                        "paginaFinal" => "566"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23159379"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anticonvulsant nature of marihuana smoking"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "P&#46;F&#46; Consroe"
                            1 => "G&#46;C&#46; Wood"
                            2 => "H&#46; Buchsbaum"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "JAMA&#46;"
                        "fecha" => "1975"
                        "volumen" => "234"
                        "paginaInicial" => "306"
                        "paginaFinal" => "307"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/808653"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0168827819306129"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "On the application of cannabis in paediatrics and epileptology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Lorenz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Neuro Endocrinol Lett&#46;"
                        "fecha" => "2004"
                        "volumen" => "25"
                        "paginaInicial" => "40"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15159680"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0261561418325901"
                          "estado" => "S300"
                          "issn" => "02615614"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Marijuana&#58; an effective antiepileptic treatment in partial epilepsy&#63; A case report and review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K&#46; Mortati"
                            1 => "B&#46; Dworetzky"
                            2 => "O&#46; Devinsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Neurol Dis&#46;"
                        "fecha" => "2007"
                        "volumen" => "4"
                        "paginaInicial" => "103"
                        "paginaFinal" => "106"
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508518303457"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alcohol and marijuana&#58; effects on epilepsy and use by patients with epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; Gordon"
                            1 => "O&#46; Devinsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2001"
                        "volumen" => "42"
                        "paginaInicial" => "1266"
                        "paginaFinal" => "1272"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy&#58; a potential role for infantile spasms and Lennox-Gastaut syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;A&#46; Hussain"
                            1 => "R&#46; Zhou"
                            2 => "C&#46; Jacobson"
                            3 => "J&#46; Weng"
                            4 => "E&#46; Cheng"
                            5 => "J&#46; Lay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yebeh.2015.04.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsy Behav&#46;"
                        "fecha" => "2015"
                        "volumen" => "47"
                        "paginaInicial" => "138"
                        "paginaFinal" => "141"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25935511"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An Australian nationwide survey on medicinal cannabis use for epilepsy&#58; history of antiepileptic drug treatment predicts medicinal cannabis use"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;S&#46; Suraev"
                            1 => "L&#46; Todd"
                            2 => "M&#46;T&#46; Bowen"
                            3 => "D&#46;J&#46; Allsop"
                            4 => "I&#46;S&#46; McGregor"
                            5 => "C&#46; Ireland"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yebeh.2017.02.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsy Behav&#46;"
                        "fecha" => "2017"
                        "volumen" => "70"
                        "paginaInicial" => "334"
                        "paginaFinal" => "340"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28238865"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Report from a survey of parents regarding the use of cannabidiol &#40;medicinal cannabis&#41; in Mexican children with refractory epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46;G&#46; Aguirre-Vel&#225;zquez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Neurol Res Int&#46;"
                        "fecha" => "2017"
                        "volumen" => "2017"
                        "itemHostRev" => array:3 [
                          "pii" => "S0168827813001347"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabinoid dose and label accuracy in edible medical cannabis products"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46; Vandrey"
                            1 => "J&#46;C&#46; Raber"
                            2 => "M&#46;E&#46; Raber"
                            3 => "B&#46; Douglass"
                            4 => "C&#46; Miller"
                            5 => "M&#46;O&#46; Bonn-Miller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "JAMA&#46;"
                        "fecha" => "2015"
                        "volumen" => "313"
                        "paginaInicial" => "2491"
                        "paginaFinal" => "2493"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "U&#46; S&#46; Food and Drug Administration&#46; Warning letters and test results for cannabidiol-related products&#46; 2016 Warning Letters &#91;Internet&#93;&#46; Silver Spring &#40;MD&#41;&#58; U&#46; S&#46; Food and Drug Administration&#46; Available from&#58; <a target="_blank" href="https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm484109.htm">https&#58;&#47;&#47;www&#46;fda&#46;gov&#47;NewsEvents&#47;PublicHealthFocus&#47;ucm484109&#46;htm</a> &#91;Accessed 26 June 2017&#93;&#46;"
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Composition and use of cannabis extracts for childhood epilepsy in the Australian community"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Suraev"
                            1 => "N&#46; Lintzeris"
                            2 => "J&#46; Stuart"
                            3 => "R&#46;C&#46; Kevin"
                            4 => "R&#46; Blackburn"
                            5 => "E&#46; Richards"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41598-018-28127-0"
                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Rep&#46;"
                        "fecha" => "2018"
                        "volumen" => "8"
                        "paginaInicial" => "10154"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29977078"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Devinsky"
                            1 => "J&#46;H&#46; Cross"
                            2 => "L&#46; Laux"
                            3 => "E&#46; Marsh"
                            4 => "I&#46; Miller"
                            5 => "R&#46; Nabbout"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1611618"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2017"
                        "volumen" => "376"
                        "paginaInicial" => "2011"
                        "paginaFinal" => "2020"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28538134"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cannabidiol in patients with seizures associated with Lennox&#8211;Gastaut syndrome &#40;GWPCARE4&#41;&#58; a randomised&#44; double-blind&#44; placebo-controlled phase 3 trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;A&#46; Thiele"
                            1 => "E&#46;D&#46; Marsh"
                            2 => "J&#46;A&#46; French"
                            3 => "M&#46; Mazurkiewicz-Beldzinska"
                            4 => "S&#46;R&#46; Benbadis"
                            5 => "C&#46; Joshi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(18)30136-3"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "2018"
                        "volumen" => "391"
                        "paginaInicial" => "1085"
                        "paginaFinal" => "1096"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29395273"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S016882781830165X"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of cannabidiol on drop seizures in the Lennox&#8211;Gastaut syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Devinsky"
                            1 => "A&#46;D&#46; Patel"
                            2 => "J&#46;H&#46; Cross"
                            3 => "V&#46; Villanueva"
                            4 => "E&#46;C&#46; Wirrell"
                            5 => "M&#46; Privitera"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2018"
                        "volumen" => "378"
                        "paginaInicial" => "1888"
                        "paginaFinal" => "1897"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug&#8211;drug interaction between clobazam and cannabidiol in children with refractory epilepsy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;L&#46; Geffrey"
                            1 => "S&#46;F&#46; Pollack"
                            2 => "P&#46;L&#46; Bruno"
                            3 => "E&#46;A&#46; Thiele"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/epi.13060"
                      "Revista" => array:7 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2015"
                        "volumen" => "56"
                        "paginaInicial" => "1246"
                        "paginaFinal" => "1251"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26114620"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0168827819306476"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coadministered cannabidiol and clobazam&#58; preclinical evidence for both pharmacodynamic and pharmacokinetic interactions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Anderson"
                            1 => "N&#46; Absalom"
                            2 => "S&#46;V&#46; Abelev"
                            3 => "I&#46;K&#46; Low"
                            4 => "P&#46;T&#46; Doohan"
                            5 => "L&#46;J&#46; Martin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/epi.16355"
                      "Revista" => array:7 [
                        "tituloSerie" => "Epilepsia&#46;"
                        "fecha" => "2019"
                        "volumen" => "60"
                        "paginaInicial" => "2224"
                        "paginaFinal" => "2234"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31625159"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0168827819302740"
                          "estado" => "S300"
                          "issn" => "01688278"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy&#58; practical experiences in a tertiary medical center"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46;S&#46; Porcari"
                            1 => "C&#46; Fu"
                            2 => "E&#46;D&#46; Doll"
                            3 => "E&#46;G&#46; Carter"
                            4 => "R&#46;P&#46; Carson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yebeh.2018.01.026"
                      "Revista" => array:6 [
                        "tituloSerie" => "Epilepsy Behav&#46;"
                        "fecha" => "2018"
                        "volumen" => "80"
                        "paginaInicial" => "240"
                        "paginaFinal" => "246"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29429908"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/21735808/0000003800000001/v1_202301170615/S2173580821001826/v1_202301170615/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "9423"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Review articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/21735808/0000003800000001/v1_202301170615/S2173580821001826/v1_202301170615/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580821001826?idApp=UINPBA00004N"
]
Article information
ISSN: 21735808
Original language: English
The statistics are updated each day
Year/Month Html Pdf Total
2024 November 14 0 14
2024 October 106 20 126
2024 September 118 21 139
2024 August 123 16 139
2024 July 143 23 166
2024 June 122 17 139
2024 May 139 32 171
2024 April 191 36 227
2024 March 237 24 261
2024 February 211 14 225
2024 January 249 24 273
2023 December 192 45 237
2023 November 206 35 241
2023 October 180 37 217
2023 September 110 32 142
2023 August 115 24 139
2023 July 116 27 143
2023 June 132 28 160
2023 May 133 27 160
2023 April 125 83 208
2023 March 51 43 94
2023 February 41 22 63
2023 January 18 20 38
2022 December 7 18 25
2022 November 18 12 30
2022 October 15 36 51
2022 September 9 14 23
2022 August 8 11 19
2022 July 11 12 23
2022 June 12 11 23
2022 May 9 4 13
2022 April 15 22 37
2022 March 33 15 48
2022 February 24 4 28
2022 January 32 14 46
2021 December 13 10 23
2021 November 4 5 9
Show all

Follow this link to access the full text of the article

es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos