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Review article
Pharmacogenetics of adverse reactions to antiepileptic drugs
Farmacogenética de reacciones adversas a fármacos antiepilépticos
I. Fricke-Galindoa, H. Jung-Cookb, A. LLerenac, M. López-Lópezd,
Corresponding author
mlopez@correo.xoc.uam.mx

Corresponding author.
a Programa de Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, México, D.F., Mexico
b Departamento de Neuropsicofarmacología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Departamento de Farmacia, Universidad Nacional Autónoma de México, Tlalpan, México, D.F., Mexico
c CICAB Centro de Investigación Clínica, Complejo Hospitalario Universitario y Facultad de Medicina, Universidad de Extremadura, Servicio Extremeño de Salud, Badajoz, Spain
d Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, México, D.F., Mexico
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This review focuses on pharmacogenetic advances in the field of ADRs caused by antiepileptic drugs &#40;AED&#41;&#44; due to their impact on treatment adherence and quality of life in epileptic patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Adverse drug reactions</span><p id="par0015" class="elsevierStylePara elsevierViewall">Adverse drug reactions are a serious problem for patients and public health systems&#46; Incidence of ADRs is estimated at 6&#46;73&#37; in the USA<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">3</span></a> and 6&#46;5&#37; in the United Kingdom&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">4</span></a> whereas in Switzerland they represent 3&#37; of deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">5</span></a> ADR prevalence has increased in patients older than 60 years&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">6</span></a> Patients with ADRs may need to be hospitalised or require longer admission times&#44; which increases treatment costs&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">7-9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">For more than 40 years&#44; the World Health Organization has defined ADRs as &#8220;a response to a drug which is noxious and unintended&#44; and which occurs at doses normally used in man for the prophylaxis&#44; diagnosis&#44; or therapy of disease&#44; or for the modifications of physiological function&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">10</span></a> Researchers have mentioned the need for a new definition to include ADRs caused by medication error&#44; unauthorised use&#44; misuse&#44; and abuse of medicinal products&#44; and the management of ADRs&#44; which includes&#44; for example&#44; the administration of a specific treatment&#44; total discontinuation of the drug&#44; and future precautionary measures&#44; among other considerations&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">11</span></a> Different types of reactions are classified from A to F&#44; with A and B being the most common types&#46; The characteristics of each type are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">11-13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Adverse reactions to antiepileptic drugs</span><p id="par0025" class="elsevierStylePara elsevierViewall">Epilepsy is one of the most prevalent neurological disorders globally&#44; affecting approximately 70 million people worldwide and at least 5 million in Latin America&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Despite numerous attempts to develop safe&#44; harmless drugs&#44; ADRs are unavoidable&#46; The different mechanisms of action of AEDs may cause undesired effects&#59; these are mainly neurological and psychiatric&#44; although other organs and systems may also be affected &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">16-31</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">ADRs during AED treatment complicate seizure control and adherence&#44; and contribute to treatment withdrawal in 25&#37; of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0705"><span class="elsevierStyleSup">32-34</span></a> In addition to affecting the patient&#39;s quality of life&#44;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">13&#44;35</span></a> there is also an economic burden associated with ADRs&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">36</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Pharmacogenetic research assesses the participation of genetic polymorphisms in response variability and susceptibility to specific types of ADR&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">2&#44;37</span></a> The study of these polymorphisms is focused on genes coding for DMEs&#44; AED transporters&#44; and&#44; more recently&#44; on the genes of the human leukocyte antigen &#40;HLA&#41; system&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">2&#44;38-40</span></a></p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Genetic polymorphisms in drug-metabolising enzymes associated with adverse reactions to antiepileptic drugs</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Phase I enzymes</span><p id="par0045" class="elsevierStylePara elsevierViewall">Type A ADRs due to AEDs include neurological and psychiatric effects&#44; vitamin deficiency&#44; endocrine disorders&#44; and hyponatraemia&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">41</span></a> Since these ADRs are dose-dependent&#44; their presence has been associated with polymorphisms in genes coding for DMEs and drug transporters&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">These enzymes are mainly responsible for metabolising endogenous and exogenous compounds&#46; For AEDs&#44; metabolic reactions are catalysed predominantly by cytochrome P450 &#40;CYP&#41; enzymes in phase I metabolism and UDP-glucuronosyltransferase &#40;UGT&#41; enzymes in phase II&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">42</span></a> Two CYP enzymes&#44; CYP2C9 and CYP2C19&#44; are important in the metabolism of phenytoin &#40;PHT&#41;&#44; a drug with a narrow therapeutic window and nonlinear pharmacokinetics&#46; CYP2C9 is responsible for 90&#37; of PHT metabolism&#44; while CYP2C19 is responsible for the remaining 10&#37;&#46; Polymorphisms in the genes coding for these cytochromes have been reported to be associated with different ADRs&#44; especially neurological effects&#46; Several allelic variants of <span class="elsevierStyleItalic">CYP2C9</span> have been described&#59; the 3 most representative and most frequently observed in white subjects are wild-type <span class="elsevierStyleItalic">CYP2C9&#42;1</span> &#40;Arg144Ile359&#41;&#44; <span class="elsevierStyleItalic">CYP2C9&#42;2</span> &#40;Cys144Ile359&#41;&#44; and <span class="elsevierStyleItalic">CYP2C9&#42;3</span> &#40;Arg144Leu359&#41;&#46; The latter 2 variants code for enzymes with decreased activity&#46; Carriers of the <span class="elsevierStyleItalic">CYP2C9&#42;2</span> genotype present an enzymatic activity of 12&#37; with regards to the wild-type <span class="elsevierStyleItalic">CYP2C9&#42;1</span>&#44; whereas enzymatic activity is only 5&#37; in <span class="elsevierStyleItalic">CYP2C9&#42;3</span> carriers&#46; In the Spanish population&#44; frequency of <span class="elsevierStyleItalic">CYP2C9&#42;2</span> and <span class="elsevierStyleItalic">CYP2C9&#42;3</span> is 16&#37; and 10&#37;&#44; respectively&#44;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">43</span></a> whereas lower frequencies are observed in Chinese and African-American populations&#44; as well as in Mexican mestizo and Mexican indigenous populations&#46;<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">44-46</span></a> Studies of African-American populations identified 2 alleles with decreased enzymatic activity&#58; <span class="elsevierStyleItalic">CYP2C9&#42;5</span> &#40;Ile359Thr&#41; and <span class="elsevierStyleItalic">&#42;6</span> &#40;c&#46;delA818&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">47&#44;48</span></a> This is important since carriers of these alleles present a poor metaboliser phenotype for PHT&#44; which may cause dizziness&#44; nystagmus&#44; ataxia&#44; excessive sedation&#44; altered level of consciousness&#44; and mental confusion&#44; negatively impacting the patient&#39;s quality of life and treatment adherence&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">49&#44;50</span></a> Several reports have described this association &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#59; however&#44; more studies into different populations&#44; including from Latin America&#44; are necessary to identify the reduced-activity variants specific to each population&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Although the Food and Drug Administration &#40;FDA&#44; the regulatory agency in the USA&#41; has not included <span class="elsevierStyleItalic">CYP2C9</span> polymorphisms in the list of pharmacogenetic biomarkers for PHT response&#44; decreasing the dose prescribed to carriers of one or 2 alleles with decreased enzymatic activity has been considered important&#44; as has monitoring the presence of ADRs and PHT plasma levels&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleItalic">CYP2C19</span> also participates in PHT metabolism&#44; although to a lesser extent&#46; <span class="elsevierStyleItalic">CYP2C19</span> alleles <span class="elsevierStyleItalic">&#42;2A</span>&#44; <span class="elsevierStyleItalic">&#42;2B</span>&#44; <span class="elsevierStyleItalic">&#42;2</span>&#44; <span class="elsevierStyleItalic">&#42;3</span>&#44; <span class="elsevierStyleItalic">&#42;4</span>&#44; <span class="elsevierStyleItalic">&#42;5A</span>&#44; <span class="elsevierStyleItalic">&#42;5B</span>&#44; <span class="elsevierStyleItalic">&#42;6</span>&#44; <span class="elsevierStyleItalic">&#42;7</span>&#44; and <span class="elsevierStyleItalic">&#42;8</span> present deficient enzymatic activity&#44; potentially increasing the likelihood of toxic effects caused by PHT&#59; however&#44; these have received less study&#46;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">55&#44;56</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Phenytoin metabolism mediated by <span class="elsevierStyleItalic">CYP2</span>C9 and <span class="elsevierStyleItalic">CYP2C19</span> causes an epoxide type intermediate&#44; which is inactivated by microsomal epoxide hydrolase &#40;EPHX1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">57</span></a> One study suggested that the teratogenic effects of PHT are due to the formation of this epoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">58</span></a> A study of maternal <span class="elsevierStyleItalic">EPHX1</span> polymorphisms in women treated with PHT and their children found that the <span class="elsevierStyleItalic">EPHX1</span> 113H and 139R polymorphisms were more frequent in mothers of children with congenital craniofacial abnormalities&#46; Researchers also observed that the maternal <span class="elsevierStyleItalic">EPHX1</span> Y113&#47;H139 haplotype showed a significant protective effect against craniofacial abnormalities in pregnancies where the mother was receiving PHT&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Phase II enzymes</span><p id="par0065" class="elsevierStylePara elsevierViewall">The glutathione S-transferase &#40;GST&#41; superfamily of phase II enzymes also participates in AED metabolism&#46; Their participation is important in the biotransformation of carbamazepine &#40;CBZ&#41; into the metabolites responsible for ADRs&#44; such as carbamazepine-10&#44;11-epoxide&#44; arene oxides&#44; and iminoquinones&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">60</span></a> A study in a Japanese population found an association between <span class="elsevierStyleItalic">GSTM1</span> null alleles and increased levels of alanine aminotransferase and aspartate transaminase in patients treated with CBZ&#46; This finding is associated with CBZ-induced hepatotoxicity&#44; an idiosyncratic and unpredictable ADR which can cause irreversible damage&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">61</span></a> A retrospective study in Japanese patients receiving valproic acid &#40;VPA&#41; reported higher levels of &#947;-glutamyltransferase in carriers of <span class="elsevierStyleItalic">GSTM1</span> null alleles&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">62</span></a> Both associations should be confirmed in Japanese and other populations to corroborate the clinical involvement of the <span class="elsevierStyleItalic">GSTM1</span> null allele in the hepatic damage caused by CBZ and&#47;or VPA&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">UGT enzymes play an important role in the removal of potentially toxic lipophilic compounds by forming glucuronides from uridine diphospho-glucuronic acid&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">63</span></a> In the case of AEDs&#44; UGT enzymes play an important role in the metabolism of CBZ&#44; lamotrigine &#40;LTG&#41;&#44; oxcarbazepine&#44; and topiramate&#44; among other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">64</span></a> Some polymorphisms in the genes coding for UGT enzymes have been reported to have an influence on inter-individual variability of the pharmacokinetic parameters of AEDs&#46; For example&#44; differences in LTG plasma levels have been associated with the <span class="elsevierStyleItalic">UGT1A4</span> L48 V variant<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">65</span></a> and differences in VPA plasma levels with the <span class="elsevierStyleItalic">UGT1A3&#42;5</span> allele&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">66</span></a> A more recent study suggested the association of <span class="elsevierStyleItalic">UGT1A6</span> 552A&#62;C polymorphism with presence of high VPA plasma levels and ADRs induced by this AED&#44; such as ataxia&#44; liver damage&#44; metabolic changes&#44; tremor&#44; hallucinations&#44; pancreatitis&#44; and excessive weight gain&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">67</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Drug transporters</span><p id="par0075" class="elsevierStylePara elsevierViewall">ABCC2 is an efflux transporter from the superfamily of ATP-binding cassette &#40;ABC&#41; transmembrane proteins&#44; which utilise the energy released by ATP hydrolysis to translocate solutes and drugs across cellular membranes&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">68</span></a> Such AEDs as PHT&#44; CBZ&#44; and VPA are substrates of this transporter&#46; Researchers have observed that when ABCC2 is overexpressed at the blood-brain barrier&#44; some patients may present refractory temporal lobe epilepsy&#46; In contrast&#44; some polymorphisms of the <span class="elsevierStyleItalic">ABCC2</span> gene may result in a decrease in the transporter&#39;s efflux function&#44; which leads to greater penetration of the drug into the brain&#44; triggering mainly neurological ADRs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0890"><span class="elsevierStyleSup">69-71</span></a> A study of Korean patients receiving VPA found that the g&#46;-1774delG polymorphism of the <span class="elsevierStyleItalic">ABCC2</span> gene was associated with presence of ADRs&#44; with patients carrying the G allele being more likely to experience dizziness&#44; headache&#44; somnolence&#44; diplopia&#44; dysarthria&#44; and tremor than those with the deletion allele &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0057&#41;&#46; Researchers also found that frequency of the T allele at g&#46;-24C&#62;T &#40;rs717620&#41; was higher in the group of patients with neurological ADRs than in the group of patients without these reactions &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0274&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">71</span></a> However&#44; other studies in Korean and Japanese populations found no association between <span class="elsevierStyleItalic">ABCC2</span> polymorphisms and VPA-related ADRs&#46;<a class="elsevierStyleCrossRefs" href="#bib0905"><span class="elsevierStyleSup">72&#44;73</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Another Korean study of patients receiving CBZ demonstrated an association between the <span class="elsevierStyleItalic">ABCC2</span> c&#46;1249G&#62;A polymorphism and presence of neurological ADRs&#46; Patients with GA or AA genotypes at this locus reported a higher frequency of neurological ADRs &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">74</span></a> An earlier report described that <span class="elsevierStyleItalic">ABCC2</span> g&#46;-1774delG polymorphism and a haplotype containing the g&#46;-1549G&#62;A&#44; g&#46;-24C&#62;T&#44; c&#46;334-49C&#62;T&#44; and c&#46;3972C&#62;T variations are a predisposing factor for developing liver complications associated with several drugs<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">75</span></a>&#59; however&#44; these have not been studied in AEDs&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">P-glycoprotein &#40;Pgp&#41;&#44; coded by the <span class="elsevierStyleItalic">ABCB1</span> gene&#44; is another transporter of the ABC superfamily&#44; and has been widely studied in the context of AED resistance and pharmacokinetic variability of substrate AEDs of human Pgp&#44; such as PHT&#44; phenobarbital&#44; and LTG&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">76</span></a> Although 3 <span class="elsevierStyleItalic">ABCB1</span> polymorphisms &#40;3435C&#62;T&#44; 2677G&#62;T&#47;A&#44; and 1236C&#62;T&#41; have been associated with variability of PHT plasma levels&#44;<a class="elsevierStyleCrossRefs" href="#bib0930"><span class="elsevierStyleSup">77&#44;78</span></a> their association with neurotoxic effects remains unclear&#46;<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">50&#44;79</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Cutaneous adverse reactions to antiepileptic drugs and their association with alleles of the HLA system</span><p id="par0090" class="elsevierStylePara elsevierViewall">Type B reactions are idiosyncratic&#44; and even though they manifest in a smaller proportion of patients&#44; they result in higher morbidity and mortality rates and require immediate withdrawal of the drug or even an additional treatment to control ADRs&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">41</span></a> These reactions include cutaneous adverse drug reactions &#40;cADR&#41;&#44; which have been reported to occur with AEDs and other drug groups&#46; These reactions have an incidence of 10 cases per 1000 new users&#46;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">80</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">There are several subtypes of cADRs&#44; with different degrees of severity&#46; Maculopapular exanthema &#40;MPE&#41; is the mildest form&#44; usually involving only the skin and not displaying systemic symptoms&#59; MPE resolves with withdrawal of the drug causing the reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">81</span></a> Drug-induced hypersensitivity syndrome &#40;DIHS&#41; and drug reaction with eosinophilia and systemic symptoms &#40;DRESS&#41; manifest between 3 weeks and 3 months after treatment onset&#59; they are characterised by skin eruption&#44; usually pruritic&#44; by lymphadenopathy&#44; fever of 38-40<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; and reactivation of human herpesvirus 6&#44; which can remain active weeks after the drug is withdrawn&#46;<a class="elsevierStyleCrossRefs" href="#bib0955"><span class="elsevierStyleSup">82&#44;83</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The most severe forms of cADR are Stevens-Johnson syndrome &#40;SJS&#41; and toxic epidermal necrolysis &#40;TEN&#41;&#44; with mortality rates of 5&#37; in SJS and 30&#37; in TEN&#44; and a calculated incidence of 2 cases per million population&#46;<a class="elsevierStyleCrossRefs" href="#bib0965"><span class="elsevierStyleSup">84&#44;85</span></a> Both syndromes are variants of a single condition&#44; but with different percentages of skin detachment &#40;less than 10&#37; in SJS and more than 30&#37; in TEN&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0975"><span class="elsevierStyleSup">86&#44;87</span></a> The most important sequelae affect the eyes&#58; up to 75&#37; of patients with TEN may present such severe ophthalmological complications as blindness&#46;<a class="elsevierStyleCrossRefs" href="#bib0985"><span class="elsevierStyleSup">88&#44;89</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Although the mechanisms causing cADRs are still to be fully defined&#44; 2 theories have been proposed&#58; the hapten&#47;prohapten theory&#44; and the hypothesis of pharmacological interactions between drugs and immune receptors &#40;p-i&#41;&#46; In the first case&#44; the drug molecule&#44; being too small to elicit an immune response&#44; acts as a hapten or prohapten&#59; it forms covalents bonds with endogenous proteins&#44; creating a hapten-carrier complex&#44; and becomes immunogenic&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">90</span></a> The hapten-carrier complex is processed by antigen presenting cells in the major histocompatibility complex &#40;MHC&#41; in the lymph nodes and other tissues&#44; which stimulates T cell production and the subsequent clinical manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">91</span></a> In contrast&#44; the p-i theory &#40;pharmacological interaction of drugs with immune receptors&#41; suggests that some drugs may bind directly and reversibly &#40;non-covalent bond&#41; to immune receptors&#44; such as the MHC or T cell receptor&#44; stimulating T cells specific to the inducing drug&#46;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">92</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In humans&#44; the genetic region of the MHC is known as the human leukocyte antigen system&#44; and comprises a group of highly polymorphic genes located at 6p21&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">93</span></a> The HLA system is conventionally divided into 3 regions known as classes I&#44; II &#40;classic molecule&#41;&#44; and III&#46; The most polymorphic exons in the genes of the classic molecule are those coding for the binding sites for peptides of class I and II HLA molecules<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">94</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Therefore&#44; pharmacogenetic research has focused in recent years on the identification of class I and &#40;to a lesser extent&#41; class II HLA alleles associated with cADRs &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">In 2004&#44; Chung et al&#46;<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">95</span></a> showed a strong association between the <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02</span> allele and CBZ-induced SJS in Chinese patients from the province of Han&#46; All patients with SJS &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>44&#41; tested positive for this allele&#44; while only 3&#37; of CBZ-tolerant patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>101&#41; and 8&#46;6&#37; of the healthy individuals &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>93&#41; carried the <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02</span> allele &#40;OR&#58; 2&#46;504&#44; 95&#37; CI&#44; 1&#46;26-49&#46;522&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; This association has been confirmed by other studies in patients from Han province&#44; as well as from central and south-east China&#44;<a class="elsevierStyleCrossRefs" href="#bib1025"><span class="elsevierStyleSup">96-98</span></a> Malaysia&#44; and Thailand&#46;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">99</span></a> This important finding led the FDA to include this information in the labelling of CBZ packaging and to recommend genetic testing for HLA alleles before starting treatment in patients of Asian descent&#46;<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">100</span></a> In contrast&#44; other studies have shown that this allele is not universal and depends upon the study population&#46; Thus&#44; no association was found between the <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02</span> allele and patients with SJS in white and Japanese populations<a class="elsevierStyleCrossRefs" href="#bib1050"><span class="elsevierStyleSup">101&#44;102</span></a>&#59; however&#44; the frequency of the <span class="elsevierStyleItalic">HLA-B&#42;15&#58;11</span> allele was reported to be higher in Japanese patients with SJS than in the general population&#46;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">103</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">An association has also been reported between the <span class="elsevierStyleItalic">HLA-A&#42;31&#58;01</span> allele and MPE or hypersensitivity syndrome &#40;HSS&#41; induced by CBZ in Chinese patients from Han province&#59; the allele was found in 25&#46;8&#37; of patients with cADRs and only 2&#46;8&#37; of CBZ-tolerant patients&#46;<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">96</span></a> This same allele was found to be associated with CBZ-induced cADRs in patients from northern European countries&#44;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">81</span></a> but no association has been found with cADRs induced by PHT or LTG&#46;<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">104</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Similarly&#44; 3 HLA haplotypes associated with AED-induced cADRs have been reported&#58; the 8&#46;1 ancestral haplotype <span class="elsevierStyleItalic">HLA-A&#42;01&#58;01&#47;-Cw&#42;07&#58;01&#47;-B&#42;08&#58;01&#47;-DRB1&#42;03&#58;01&#47;-DQA1&#42;05&#58;01&#47;-DQB1&#42;02&#58;01</span>&#44; associated with CBZ-induced HSS in white populations<a class="elsevierStyleCrossRef" href="#bib1085"><span class="elsevierStyleSup">108</span></a>&#59; and <span class="elsevierStyleItalic">HLA-A&#42;24&#58;01&#47;-B&#42;59&#58;01&#47;-C&#42;01&#58;02</span> and <span class="elsevierStyleItalic">HLA-A&#42;02&#58;01&#47;-B&#42;15&#58;18&#47;-C&#42;07&#58;04</span>&#44; with high relative risk values for severe cADRs induced by CBZ in Japanese patients &#40;16&#46;09 and 28&#46;94&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1090"><span class="elsevierStyleSup">109</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The association of genetic variants close to the HLA-E locus &#40;rs1264511&#41; and the motilin &#40;rs2894342&#41; and the <span class="elsevierStyleItalic">CYP2B6</span> genes &#40;rs1042389&#41; with the presence of CBZ-induced cADRs has also been reported in a Han Chinese population&#59; however&#44; these results were not robust&#46;<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">96</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusion</span><p id="par0135" class="elsevierStylePara elsevierViewall">The data reviewed show that interethnic variability has a strong effect on the association of genetic polymorphisms with presence of AED-induced ADRs&#46; To date&#44; research into the <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02</span> allele and its relationship with CBZ-induced cADRs in patients of Asian birth or descent has been essential in the pharmacogenetic study of ADRs induced by antiepileptics&#46; Therefore&#44; such regulatory agencies as the FDA have considered this allele a pharmacogenetic biomarker for these populations&#46; Nevertheless&#44; there continues to be controversy regarding the replication of results in other populations&#44; including Asian populations&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Another important finding in the pharmacogenetics of AEDs is the association of <span class="elsevierStyleItalic">CYP2C9&#42;2</span> and <span class="elsevierStyleItalic">&#42;3</span> alleles with the development of neurological ADRs due to decreased enzymatic activity of CYP2C9&#46; Furthermore&#44; <span class="elsevierStyleItalic">ABCC2</span> variants are gaining importance in the presence of ADRs since they participate in the transport of AEDs across the blood-brain barrier&#59; however&#44; this association has not been demonstrated sufficiently&#46; Assessing the participation of genes coding for AED receptors&#44; such as <span class="elsevierStyleItalic">SCN1A</span>&#44; <span class="elsevierStyleItalic">SCN2A</span>&#44; and <span class="elsevierStyleItalic">GABRA1</span>&#44; in the appearance of ADRs may also be an interesting line of research&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The identification of pharmacogenetic biomarkers enabling undesired effects of AEDs to be predicted would help increase safety when prescribing these drugs&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0150" class="elsevierStylePara elsevierViewall">This review article was drafted as part of a project funded by the Consejo Nacional de Ciencia y Tecnolog&#237;a &#40;CONACYT &#35;167261&#41; of Mexico and the doctoral research grant &#40;CONACYT &#35;369708&#41; awarded to Ingrid Fricke-Galindo&#46; This study was coordinated within the Red Iberoamericana de Farmacogen&#233;tica y Farmacogen&#243;mica &#40;SIFF-RIBEF <a id="intr0010" class="elsevierStyleInterRef" href="http://www.ribef.com/">www&#46;ribef&#46;com</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Adverse drug reactions"
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              "titulo" => "Adverse reactions to antiepileptic drugs"
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          "titulo" => "Genetic polymorphisms in drug-metabolising enzymes associated with adverse reactions to antiepileptic drugs"
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              "titulo" => "Phase I enzymes"
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          "titulo" => "Cutaneous adverse reactions to antiepileptic drugs and their association with alleles of the HLA system"
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            0 => "Farmacogen&#233;tica"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Adverse drug reactions &#40;ADRs&#41; are a major public health concern and a leading cause of morbidity and mortality in the world&#46; In the case of antiepileptic drugs &#40;AEDs&#41;&#44; ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients&#8217; quality of life of patients&#46; Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety&#46; This article presents a review of genes coding for drug metabolising enzymes and drug transporters&#44; and HLA system genes that have been linked to AED-induced ADRs&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Development</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To date&#44; several genetic variations associated with drug safety have been reported&#58; <span class="elsevierStyleItalic">CYP2C9&#42;2</span> and <span class="elsevierStyleItalic">&#42;3</span> alleles&#44; which code for enzymes with decreased activity&#44; have been linked to phenytoin &#40;PHT&#41;-induced neurotoxicity&#59; <span class="elsevierStyleItalic">GSTM1</span> null alleles with hepatotoxicity induced by carbamazepine &#40;CBZ&#41; and valproic acid &#40;VPA&#41;&#59; <span class="elsevierStyleItalic">EPHX1</span> polymorphisms with teratogenesis&#59; <span class="elsevierStyleItalic">ABCC2</span> genetic variations with CBZ- and VPA-induced neurological ADRs&#59; and <span class="elsevierStyleItalic">HLA</span> alleles &#40;e&#46;g&#46; <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02</span>&#44; <span class="elsevierStyleItalic">-A&#42;31&#58;01</span>&#44; <span class="elsevierStyleItalic">-B&#42;15&#58;11</span>&#44; <span class="elsevierStyleItalic">-C&#42;08&#58;01</span>&#41; with cutaneous ADRs&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability&#44; which indicates a need for future studies in different populations to gather more useful results for larger number of patients&#46; The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy&#46;</p></span>"
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            "titulo" => "Introduction"
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        "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introducci&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Las reacciones adversas a medicamentos &#40;RAM&#41; son un problema de salud p&#250;blica y una importante causa de morbimortalidad a nivel mundial&#46; En el caso de los f&#225;rmacos antiepil&#233;pticos &#40;FAE&#41;&#44; la presencia de RAM puede ser un impedimento para lograr el &#233;xito terap&#233;utico al dificultar la adherencia al tratamiento e impactar la calidad de vida del paciente&#46; La farmacogen&#233;tica busca la identificaci&#243;n de variantes gen&#233;ticas asociadas a la seguridad de los f&#225;rmacos&#46; En este art&#237;culo se revisan los genes que codifican para enzimas metabolizadoras y transportadores de f&#225;rmacos&#44; as&#237; como en el sistema HLA asociados a RAM inducidas por FAE&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Desarrollo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A la fecha&#44; se ha reportado la asociaci&#243;n de los alelos <span class="elsevierStyleItalic">CYP2C9&#42;2</span> y <span class="elsevierStyleItalic">&#42;3</span>&#44; que codifican para enzimas de actividad reducida&#44; con efectos neurot&#243;xicos por fenito&#237;na &#40;PHT&#41;&#59; alelos nulos de <span class="elsevierStyleItalic">GSTM1</span> asociados con hepatotoxicidad inducida por carbamazepina &#40;CBZ&#41; y &#225;cido valproico &#40;VPA&#41;&#59; polimorfismos gen&#233;ticos de <span class="elsevierStyleItalic">EPHX1</span> en la teratog&#233;nesis inducida por PHT&#59; variantes gen&#233;ticas de <span class="elsevierStyleItalic">ABCC2</span> asociadas con RAM neurol&#243;gicas por CBZ y VPA&#44; y tambi&#233;n diversos alelos de HLA &#40;p&#46; ej&#46;&#44; <span class="elsevierStyleItalic">HLA-B&#42;15&#58;02&#44; -A&#42;31&#58;01&#44; -B&#42;15&#58;11&#44; -C&#42;08&#58;01</span>&#41; asociados con RAM de tipo cut&#225;neas&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Los hallazgos publicados muestran que existen RAM con base farmacogen&#233;tica con una alta variabilidad inter&#233;tnica&#44; lo que refleja la necesidad de que se realicen estudios en distintas poblaciones para poder obtener resultados que sean de utilidad a un n&#250;mero mayor de pacientes&#46; La b&#250;squeda de biomarcadores que permitan la predicci&#243;n de RAM a FAE podr&#237;a mejorar la farmacoterapia en la epilepsia&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as&#58; Fricke-Galindo I&#44; Jung-Cook H&#44; LLerena A&#44; L&#243;pez-L&#243;pez M&#46; Farmacogen&#233;tica de reacciones adversas a f&#225;rmacos antiepil&#233;pticos&#46; Neurolog&#237;a&#46; 2018&#59;33&#58;165&#8211;176&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Participation of the ABCB1 and ABCC2 transporters at the blood-brain barrier &#40;BBB&#41; in the development of adverse reactions to antiepileptic drugs&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">HLA class I and II genes and alleles&#58; organisation of HLA system genes&#59; &#40;above&#41; exons are shown as squares and introns as lines&#59; above the squares are labels indicating the HLA molecule domains &#40;depicted below&#41; coded for by each exon&#59; exons shown in white are those that contain the majority of the polymorphisms included in these genes&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AED&#58; antiepileptic drug&#59; ADR&#58; adverse drug reaction&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Taken from Edwards and Aronson&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">11</span></a> Scott and Thompson&#44;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">12</span></a> and Perucca and Gilliam&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">13</span></a></p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ADR type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Examples of AED-induced ADRs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dose-dependent&#59; excessive pharmacological response&#59; predictable&#44; reversible&#44; frequent&#59; low severity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&#44; headache&#44; tremor&#44; somnolence&#44; insomnia&#44; vertigo&#44; ataxia&#44; diplopia&#44; depression&#44; hyponaetremia&#44; paraesthesias&#44; gastrointestinal disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unrelated to dose or pharmacological mechanism of action&#59; related to individual vulnerability&#59; unpredictable&#59; not frequent&#44; high morbidity and mortality rates&#59; reversible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cutaneous and hypersensitivity reactions &#40;Stevens-Johnson syndrome&#44; toxic epidermal necrolysis&#44; mild maculopapular exanthema&#44; etc&#46;&#41;&#44; hepatotoxicity&#44; aplastic anaemia&#44; agranulocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Related to dose and time &#40;dose accumulation&#41;&#59; not frequent&#59; chronic&#59; most are reversible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weight gain or loss&#44; gingival enlargement&#44; vision loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Related to time&#44; usually to dose and prenatal exposure&#59; not frequent&#59; irreversible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Teratogenesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Related to drug withdrawal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insomnia&#44; anxiety&#44; and disturbances after sudden withdrawal of benzodiazepines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unexpected treatment failure&#59; frequent&#59; related to dose and drug interaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decreased plasma levels of drugs due to enzyme induction of concomitant treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classification of adverse drug reactions&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">DRESS&#58; drug reaction with eosinophilia and systemic symptoms&#59; HSS&#58; hypersensitivity syndrome&#59; MPE&#58; maculopapular exanthema&#59; NR&#58; reactions not frequently reported for these antiepileptic drugs&#59; SJS&#58; Stevens-Johnson syndrome&#59; TEN&#58; toxic epidermal necrolysis&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Antiepileptic drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of adverse reaction</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Neurological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cutaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Other&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Eslicarbazepine acetate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&#44; somnolence&#44; headache&#44; insomnia&#44; tremor&#44; diplopia&#44; instability&#44; behavioural disorders&#44; and learning disabilities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hyponatraemia&#44; anorexia&#44; nausea&#44; vomiting&#44; diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Valproic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of memory&#44; tremor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weight gain&#44; hepatotoxicity<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#44; teratogenesis<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of memory&#44; dizziness&#44; somnolence&#44; instability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#44; TEN&#44; DRESS&#44; HSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hyponatraemia&#44; nausea&#44; vomiting&#44; teratogenesis<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clobazam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; dizziness&#44; irritability&#44; ataxia&#44; vertigo&#44; headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersalivation&#44; weight gain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clonazepam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; dizziness&#44; ataxia&#44; loss of memory&#44; depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Upper respiratory tract infection&#44; sinusitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethosuximide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; ataxia&#44; headache&#44; difficulty concentrating&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&#44; vomiting&#44; leukopoenia&#44; indigestion&#44; diarrhoea&#44; weight loss&#44; hiccups&#44; anorexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phenytoin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; loss of memory&#44; mood swings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#44; TEN&#44; DRESS&#44; HSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gingival hyperplasia&#44; hirsutism&#44; teratogenesis<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phenobarbital&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; dizziness&#44; loss of memory&#44; mood swings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#44; SJS<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#44; TEN<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gabapentin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; dizziness&#44; ataxia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DRESSb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Joint pain&#44; muscle pain&#44; dry mouth&#44; nausea&#44; diarrhoea&#44; peripheral oedema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lacosamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&#44; ataxia&#44; diplopia&#44; vertigo&#44; ataxia&#44; tremor&#44; headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPEb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&#44; vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lamotrigine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of memory&#44; somnolence&#44; dizziness&#44; ataxia&#44; diplopia&#44; headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#44; TEN&#44; MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rhinitis&#44; nausea&#44; teratogenesis<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Levetiracetam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; depression&#44; diplopia&#44; dizziness&#44; fatigue&#44; headache&#44; depression&#44; nervousness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SSJ<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pharyngitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of memory&#44; somnolence&#44; headache&#44; diplopia&#44; fatigue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#44; TEN&#44; DRESS&#44; HSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nausea&#44; vomiting&#44; hyponatraemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Perampanel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&#44; ataxia&#44; somnolence&#44; irritability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Weight gain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pregabalin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dizziness&#44; somnolence&#44; vertigo&#44; blurred vision&#44; difficulty concentrating&#44; ataxia&#44; fatigue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dry mouth&#44; oedema&#44; weight gain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Topiramate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Somnolence&#44; dizziness&#44; fatigue&#44; learning difficulties&#44; instability&#44; paraesthesias&#44; difficulty concentrating&#44; difficulty speaking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anorexia&#44; weight loss&#44; nephrolithiasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zonisamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Irritability&#44; confusion&#44; ataxia&#44; dizziness&#44; depression&#44; difficulty concentrating&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#44; TEN&#44; MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrolithiasis&#44; anorexia&#44; weight loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Frequent reactions were those manifesting in &#8805;<span class="elsevierStyleHsp" style=""></span>1&#47;100 to &#60;<span class="elsevierStyleHsp" style=""></span>1&#47;10 of the patients&#44; and very frequent reactions&#44; those reported by &#8805;<span class="elsevierStyleHsp" style=""></span>1&#47;10 patients&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">These adverse reactions manifest at a frequency of &#8805;<span class="elsevierStyleHsp" style=""></span>1&#47;100&#59; however&#44; they were included due to their severity and their significance in pharmacogentics&#46;</p> <p class="elsevierStyleNotepara" id="npar0015">Taken from Brogden et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">16</span></a> Greenwood&#44;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">17</span></a> Herranz et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">18</span></a> Hill et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">19</span></a> Jarernsiripornkul et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">20</span></a> Ketter et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">21</span></a> Massot et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">22</span></a> Pellock&#44;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">23</span></a> Posner et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">24</span></a> Tomson and Battino&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">25</span></a> Riverol et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">26</span></a> Zaccara et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">27-31</span></a></p>"
            ]
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Frequent and very frequent<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> adverse reactions to antiepileptic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">16-31</span></a></p>"
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        "etiqueta" => "Table 3"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Pl&#58; plasma levels&#59; UD&#58; undetermined&#59; US&#58; unspecified&#59; ADR&#58; adverse drug reaction&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">CYP2C9</span> genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">CYP2C19</span> genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Assessed phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ADR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;6&#47;&#42;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#42;1&#47;&#42;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">African-American&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neurotoxicity<br>Half-life &#40;13 days&#41;&#44; clearance &#40;17&#37; of that observed in other patients with normal enzymatic activity&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mental confusion&#44; dysarthria&#44; loss of memory&#44; astasia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kidd et al&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;1&#47;&#42;2<br>or &#42;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">US&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">White&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Drug response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">All types of ADRs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pharmacogenetic study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Depondt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;2&#47;&#42;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#42;1&#47;&#42;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">White&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neurotoxicity and Pl &#40;69<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vertigo&#44; ataxia&#44; nystagmus&#44; sedation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dorado et al&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;3&#47;&#42;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">UD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Toxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gingival enlargement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Babu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;1&#47;&#42;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#42;1&#47;&#42;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Japanese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pl &#40;32&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ataxia&#44; diplopia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ninomiya et al&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#42;3&#47;&#42;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">UD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Toxicity and Pl &#40;33&#46;2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nystagmus&#44; ataxia&#44; sedation&#44; hirsutism&#44; lymphadenopathy&#44; anaemia&#44; gingival enlargement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ramasamy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">CBZ&#58; carbamazepine&#59; DIHS&#58; drug-induced hypersensitivity syndrome&#59; AED&#58; antiepileptic drug&#59; HLA&#58; human leukocyte antigen&#59; HSS&#58; hypersensitivity syndrome&#59; CI&#58; confidence interval&#59; LTG&#58; lamotrigine&#59; MPE&#58; maculopapular exanthema&#59; NR&#58; not reported&#59; OR&#58; odds ratio&#59; OXC&#58; oxcarbazepine&#59; PHT&#58; phenytoin&#59; cADR&#58; cutaneous adverse drug reaction&#59; SJS&#58; Stevens-Johnson syndrome&#59; TEN&#58; toxic epidermal necrolysis&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AED causing cADRs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HLA allele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">cADR subtype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CBZ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">B&#42;15&#58;02</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#47;TEN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Han Chinese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;13 E-27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">126-495&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chung et al&#46;<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">95</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Thai&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;28-181&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tangamornsukan et al&#46;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">99</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Malaysian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">221&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;85-12<span class="elsevierStyleHsp" style=""></span>694&#46;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">B&#42;15&#58;11</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#47;TEN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Japanese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;0263&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;01-47&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kaniwa et al&#46;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">103</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">A&#42;31&#58;01</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE&#47;HSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Han Chinese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;0021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;6-41&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hung et al&#46;<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">96</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#47;TEN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Northern Europe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 E-5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;93-116&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">McCormack et al&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">81</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#47;TEN&#47;DIHS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Japanese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;4 E-15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;9-19&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ozeki et al&#46;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">105</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">A&#42;02&#58;01</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Han Chinese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;033&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">106</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PHT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">B&#42;15&#58;02</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SJS&#47;TEN&#47;HSS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">B&#42;15&#58;02</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Cost evaluation of adverse drug reactions in hospitalized patients in Taiwan&#58; a prospective&#44; descriptive&#44; observational study"
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Article information
ISSN: 21735808
Original language: English
DOI:10.1016/j.nrleng.2015.03.021
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