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schizophrenia and psychosis. Its use is reserved for patients who have failed to respond to or cannot tolerate other antipsychotics.</p><p>Thioridazine has been shown to prolong the QT interval (the time taken for the heart ventricles to depolarize and repolarize) in a dose related manner. Drugs with this potential have been associated with the life-threatening ventricular tachycardia, “torsades de pointes”.</p><p>The CYP2D6 enzyme is involved in metabolizing thioridazine. About 7% of the population has reduced enzyme activity because of variants in the <i>CYP2D6</i> gene. In individuals with low CYP2D6 activity, standard doses of thioridazine may lead to higher drug levels in the plasma, and increase the risk of cardiac arrhythmias.</p><p>The FDA-approved drug label for thioridazine states that thioridazine is contraindicated in individuals who are known to have reduced levels of CYP2D6 activity. The label also states it is contraindicated to coadminister thioridazine with drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) or inhibit the metabolism of thioridazine (e.g., fluvoxamine, propranolol, and pindolol) (<a class="bibr" href="#thioridazine.REF.1" rid="thioridazine.REF.1">1</a>).</p></div><div id="thioridazine.Drug_Class_Antipsychotics"><h2 id="_thioridazine_Drug_Class_Antipsychotics_">Drug Class: Antipsychotics</h2><p>The first antipsychotics to be discovered in the 1950s were haloperidol and chlorpromazine, followed by other agents, including fluphenazine, loxapine, pherphenazine, pimozide, thioridazine, thiothixene, and trifluoperazine.</p><p>Known as “first generation” or “typical” antipsychotics, these drugs were used to treat psychosis (regardless of the cause), chronic psychotic disorders (e.g., schizophrenia), and other psychiatric conditions. However, prominent adverse effects included extrapyramidal side effects such as tardive dyskinesia, muscle rigidity, and tremors, i.e., Parkinsonian-like symptoms.</p><p>Newer antipsychotics, known as “second generation” or “atypical” antipsychotics, have a lower risk of extrapyramidal side effects. However, many have serious metabolic effects. These antipsychotics include aripiprazole, clozapine, iloperidone, olanzapine, and risperidone.</p></div><div id="thioridazine.Drug_Thioridazine"><h2 id="_thioridazine_Drug_Thioridazine_">Drug: Thioridazine</h2><p>Thioridazine is a first generation “typical” antipsychotic used in the treatment of schizophrenia. Schizophrenia is a severe neurodevelopmental disorder with a worldwide prevalence of around 0.3˗0.7% (<a class="bibr" href="#thioridazine.REF.2" rid="thioridazine.REF.2">2</a>). The etiology of schizophrenia is unknown, but it is thought to result from a combination of complex genetic and environmental factors. Before the discovery of the first antipsychotics in the 1950s, the management of schizophrenia relied heavily upon sedation, electroconvulsive therapy, and institutionalization.</p><p>The symptoms of schizophrenia fall into three main categories: positive, negative, and cognitive. Positive symptoms are generally not found in healthy individuals, but may come and go or persist in individuals with schizophrenia. Positive symptoms include reality distortion (e.g., delusions, hallucinations), and thought disorders. These symptoms often respond well to treatment.</p><p>Negative symptoms are deficits in normal emotions and behavior, and may be mistaken for depression. Symptoms divide into reduced expression of emotion (e.g., speaking without moving or with a monotonous voice) and avolition (a lack of motivation to start or continue with a task). No treatment has established efficacy for these pathologies.</p><p>Cognitive symptoms may also be difficult to recognize. They include poor executive functioning (understanding information and using it to make decisions) and trouble focusing or paying attention. And again, no treatment has established efficacy.</p><p>The use of thioridazine is reserved for patients who have failed to respond to or cannot tolerate the side effects of other antipsychotics. The FDA-approved drug label for thioridazine strongly recommends that prior to starting thioridazine, a patient should be given at least two trials, each with a different antipsychotic drug product, at an adequate dose, for an adequate duration of time. The label also states that for patients who do require chronic treatment with thioridazine, the smallest dose and the shortest duration of treatment should be sought and the need for continued treatment should be reassessed periodically; and cautions that the efficacy of thioridazine in treating patients with refractory schizophrenia is unknown (<a class="bibr" href="#thioridazine.REF.1" rid="thioridazine.REF.1">1</a>).</p><p>The main action of both first-generation and second-generation antipsychotics appears to be the post-synaptic blockade of D2 dopamine receptors in the brain. (An exception is aripiprazole, which is a D2 partial agonist.) Blockade of the D2 receptor in the brain’s limbic system is thought to improve the “positive” symptoms of schizophrenia (<a class="bibr" href="#thioridazine.REF.3" rid="thioridazine.REF.3">3</a>).</p><p>However, because the first-generation antipsychotics also block dopamine receptors in the nigrostriatal pathway, they cause movement disorders known as extrapyramidal side effects. These disorders include akathisia (motor restlessness), dystonia (abnormal muscle tone), and tardive dyskinesia (involuntary and repetitive movements).</p><p>Compared to other first generation antipsychotics, thioridazine shares a similar efficacy, but has a lower risk of extrapyramidal side effects (<a class="bibr" href="#thioridazine.REF.4" rid="thioridazine.REF.4">4</a>, <a class="bibr" href="#thioridazine.REF.5" rid="thioridazine.REF.5">5</a>, <a class="bibr" href="#thioridazine.REF.6" rid="thioridazine.REF.6">6</a>). However, a higher level of EKG changes is associated with thioridazine therapy (<a class="bibr" href="#thioridazine.REF.6" rid="thioridazine.REF.6">6</a>).</p><p>Antipsychotics, and thioridazine in particular, can inhibit cardiac ion channels. Most first generation antipsychotics block the cardiac potassium channel KCNH2, previously known as the human ether-a-go-go-related gene (hERG) (<a class="bibr" href="#thioridazine.REF.7" rid="thioridazine.REF.7">7</a>, <a class="bibr" href="#thioridazine.REF.8" rid="thioridazine.REF.8">8</a>). Blockade of this channel reduces inward potassium current, resulting in longer cardiac repolarization times. On the EKG, this manifests as a prolonged QT interval. In extreme cases, this can lead to a life-threatening ventricular tachycardia known as torsades de pointes (“twisting of the points”) (<a class="bibr" href="#thioridazine.REF.9" rid="thioridazine.REF.9">9</a>, <a class="bibr" href="#thioridazine.REF.10" rid="thioridazine.REF.10">10</a>, <a class="bibr" href="#thioridazine.REF.11" rid="thioridazine.REF.11">11</a>).</p><p>At one point, thioridazine was one of the most commonly used medications for major mental health disorders. However, numerous case reports of sudden, unexpected death led to label changes in 2000, which recommended that thioridazine be used as a last resort (<a class="bibr" href="#thioridazine.REF.12" rid="thioridazine.REF.12">12</a>). In 2005, the manufacturer Novartis discontinued the branded form of thioridazine because of its association with QT prolongation, but generic forms are still available in the US (<a class="bibr" href="#thioridazine.REF.13" rid="thioridazine.REF.13">13</a>).</p><p>Thioridazine is metabolized by CYP2D6 to the active metabolite mesoridazine, which is further metabolized to sulforidazine, both of which are more potent than thioridazine. In addition, both thioridazine and mesoridazine have similar effects on the QT interval (<a class="bibr" href="#thioridazine.REF.14" rid="thioridazine.REF.14">14</a>, <a class="bibr" href="#thioridazine.REF.15" rid="thioridazine.REF.15">15</a>).</p><p>Recent research has found that thioridazine is active against multidrug resistant tuberculosis, when used in combination with other antituberculosis drugs. Thioridazine increases the permeability of the cell-envelope, enabling the enhanced uptake of antibiotics (<a class="bibr" href="#thioridazine.REF.16" rid="thioridazine.REF.16">16</a>).</p><p>The FDA drug label states that no teratogenic effect has been shown with thioridazine to date. However, all drugs should be kept to a minimum during pregnancy, so thioridazine should be given only when the benefits exceed the possible risks to mother and fetus. Of note, neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery which vary in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.</p></div><div id="thioridazine.The_Cytochrome_P450_Superfa"><h2 id="_thioridazine_The_Cytochrome_P450_Superfa_">The Cytochrome P450 Superfamily</h2><p>The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs. The <i>CYP450</i> genes are very polymorphic and can result in reduced, absent, or increased enzyme activity.</p></div><div id="thioridazine.Gene_CYP2D6"><h2 id="_thioridazine_Gene_CYP2D6_">Gene: <i>CYP2D6</i></h2><p><i>CYP2D6</i> is highly polymorphic; over 100 star (*) alleles are described and currently catalogued at the Pharmacogene Variation (<a href="https://www.pharmvar.org/gene/CYP2D6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PharmVar</a>) database (<a class="bibr" href="#thioridazine.REF.17" rid="thioridazine.REF.17">17</a>). <i>CYP2D6*1</i> is the reference (or wild-type) allele encoding enzyme with normal activity. The <i>CYP2D6*2</i>, *<i>33</i>, and <i>*35</i> alleles are also considered to confer normal activity (<a href="/books/NBK424018/table/thioridazine.T.activity_status_of_select/?report=objectonly" target="object" rid-ob="figobthioridazineTactivitystatusofselect">Table 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figthioridazineTactivitystatusofselect"><a href="/books/NBK424018/table/thioridazine.T.activity_status_of_select/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobthioridazineTactivitystatusofselect"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="thioridazine.T.activity_status_of_select"><a href="/books/NBK424018/table/thioridazine.T.activity_status_of_select/?report=objectonly" target="object" rid-ob="figobthioridazineTactivitystatusofselect">Table 1. </a></h4><p class="float-caption no_bottom_margin">Activity status of selected <i>CYP2D6</i> alleles </p></div></div><p>An activity score can be assigned to each <i>CYP2D6</i> allele, e.g., 1 for each functional allele, 0.5 for a decreased function allele, and 0 for a no function allele. Individuals who carry more than two normal function copies (e.g., multiple copies) of the <i>CYP2D6</i> gene are “ultrarapid metabolizers”, whereas individuals who are “normal metabolizers” either carry two normal function copies of <i>CYP2D6</i>, or a combination of normal/decreased/no function alleles that result in an activity score between 1.0 and 2.0. Individuals who are intermediate or poor metabolizers carry copies of decreased or no function <i>CYP2D6</i> alleles, respectively (<a href="/books/NBK424018/table/thioridazine.T.2016_assignment_of_cyp2d6/?report=objectonly" target="object" rid-ob="figobthioridazineT2016assignmentofcyp2d6">Table 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figthioridazineT2016assignmentofcyp2d6"><a href="/books/NBK424018/table/thioridazine.T.2016_assignment_of_cyp2d6/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobthioridazineT2016assignmentofcyp2d6"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="thioridazine.T.2016_assignment_of_cyp2d6"><a href="/books/NBK424018/table/thioridazine.T.2016_assignment_of_cyp2d6/?report=objectonly" target="object" rid-ob="figobthioridazineT2016assignmentofcyp2d6">Table 2. </a></h4><p class="float-caption no_bottom_margin">2016 Assignment of <i>CYP2D6</i> phenotypes by CPIC </p></div></div><p>The most common no function alleles include <i>CYP2D6*3</i>, <i>*4</i>, <i>*5</i>, and <i>*6</i> (<a class="bibr" href="#thioridazine.REF.19" rid="thioridazine.REF.19">19</a>, <a class="bibr" href="#thioridazine.REF.20" rid="thioridazine.REF.20">20</a>, <a class="bibr" href="#thioridazine.REF.21" rid="thioridazine.REF.21">21</a>, <a class="bibr" href="#thioridazine.REF.22" rid="thioridazine.REF.22">22</a>), and the most common decreased function alleles include <i>CYP2D6*9, *10, *17, *29</i> and <i>*41</i> (<a class="bibr" href="#thioridazine.REF.23" rid="thioridazine.REF.23">23</a>, <a class="bibr" href="#thioridazine.REF.24" rid="thioridazine.REF.24">24</a>, <a class="bibr" href="#thioridazine.REF.25" rid="thioridazine.REF.25">25</a>, <a class="bibr" href="#thioridazine.REF.26" rid="thioridazine.REF.26">26</a>, <a class="bibr" href="#thioridazine.REF.27" rid="thioridazine.REF.27">27</a>) .There are large inter-ethnic differences in the frequency of these alleles. For example, <i>CYP2D6*4</i> is the most common no function allele in Caucasians, but is less abundant in subjects with African ancestry, and is rare in Asians. In contrast, the decreased function allele <i>CYP2D6*10</i> is the most common allele in Asians, and <i>CYP2D6</i>*<i>17</i> is almost exclusively found in individuals with African ancestry (<a class="bibr" href="#thioridazine.REF.28" rid="thioridazine.REF.28">28</a>).</p><p>Consequently, the phenotype frequencies also vary substantially among the major ethnicities and may vary among populations. Approximately 6-10% of European Caucasians and their descendants are poor metabolizers, mainly due to the prevalent no function <i>CYP2D6*4</i> and <i>*5</i> alleles (<a class="bibr" href="#thioridazine.REF.29" rid="thioridazine.REF.29">29</a>, <a class="bibr" href="#thioridazine.REF.30" rid="thioridazine.REF.30">30</a>).</p><p>In individuals who are <i>CYP2D6</i> poor metabolizers, standard doses of thioridazine may lead to the drug accumulating in the plasma. Since a dose-related side effect of thioridazine is prolongation of the QTc interval, which is a potentially life threatening event, the FDA has stated that the use of thioridazine is contraindicated in individuals who are known to have reduced CYP2D6 activity (<a class="bibr" href="#thioridazine.REF.1" rid="thioridazine.REF.1">1</a>, <a class="bibr" href="#thioridazine.REF.31" rid="thioridazine.REF.31">31</a>). In addition, the label also states it is contraindicated to coadminister thioridazine with other drugs that inhibit CYP2D6 activity (e.g., the antidepressants fluoxetine and paroxetine) or inhibit the metabolism of thioridazine (e.g., the beta-blockers propranolol and pindolol, and the antidepressant fluvoxamine) (<a class="bibr" href="#thioridazine.REF.1" rid="thioridazine.REF.1">1</a>).</p></div><div id="thioridazine.Genetic_Testing"><h2 id="_thioridazine_Genetic_Testing_">Genetic Testing</h2><p>The NIH’s Genetic Testing Registry, GTR, provides examples of the genetic tests that are currently available for the <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=CN078018" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">thioridazine response</a> and the <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=1565%5bgeneid%5d" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CYP2D6 gene</a>.</p><p>Results are typically reported as a diplotype, such as <i>CYP2D6 *1/*1</i>. A result for copy number, if available, is also important when interpreting <i>CYP2D6</i> results (<a class="bibr" href="#thioridazine.REF.32" rid="thioridazine.REF.32">32</a>). However, it needs to be noted that the number of variants tested varies substantially among laboratories and there is no standardized way to report results (<a class="bibr" href="#thioridazine.REF.33" rid="thioridazine.REF.33">33</a>).</p><p>If the test results include an interpretation of the patient’s predicted metabolizer phenotype, this should be confirmed by checking the diplotype and assigning an activity score to each allele (e.g., 0 for no function, 0.5 for decreased function, and 1 for each copy of a normal function allele). The phenotype is defined by the sum of the two scores:</p><ul><li class="half_rhythm"><div>An extensive (normal) metabolizer phenotype has an activity score of 1 to 2</div></li><li class="half_rhythm"><div>An intermediate metabolizer has an activity score of 0.5</div></li><li class="half_rhythm"><div>A poor metabolizer has an activity score of 0</div></li><li class="half_rhythm"><div>An ultrarapid metabolizer has an activity score of greater than 2 (<a class="bibr" href="#thioridazine.REF.18" rid="thioridazine.REF.18">18</a>, <a class="bibr" href="#thioridazine.REF.34" rid="thioridazine.REF.34">34</a>)</div></li></ul></div><div id="thioridazine.Therapeutic_Recommendations"><h2 id="_thioridazine_Therapeutic_Recommendations_">Therapeutic Recommendations based on Genotype</h2><p><b>This section contains excerpted</b><sup><a href="#thioridazine.FN1">1</a></sup>
|
|
<b>information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.</b></p><p><b>2016 Statement from the US Food and Drug Administration (FDA):</b> Reduced cytochrome P450 2D6 isozyme activity drugs that inhibit this isozyme (e.g., fluoxetine and paroxetine) and certain other drugs (e.g., fluvoxamine, propranolol, and pindolol) appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as Torsades de pointes type arrhythmias. Such an increased risk may result also from the additive effect of coadministering thioridazine with other agents that prolong the QTc interval. Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6.</p><p><b>Please review the complete therapeutic recommendations that are located here: (</b><a class="bibr" href="#thioridazine.REF.1" rid="thioridazine.REF.1"><b>1</b></a><b>)</b>.</p></div><div id="thioridazine.Nomenclature"><h2 id="_thioridazine_Nomenclature_">Nomenclature</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figthioridazineTnomenclatureofselected"><a href="/books/NBK424018/table/thioridazine.T.nomenclature_of_selected/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobthioridazineTnomenclatureofselected"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="thioridazine.T.nomenclature_of_selected"><a href="/books/NBK424018/table/thioridazine.T.nomenclature_of_selected/?report=objectonly" target="object" rid-ob="figobthioridazineTnomenclatureofselected">Table</a></h4><p class="float-caption no_bottom_margin">Nomenclature of selected <i>CYP2D6</i> alleles </p></div></div><p>Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS) (<a class="bibr" href="#thioridazine.REF.35" rid="thioridazine.REF.35">35</a>)</p><p>Nomenclature for Cytochrome P450 enzymes is available from the Pharmacogene Variation Consortium (PharmVar) <a href="https://www.pharmvar.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.pharmvar.org/</a>.</p></div><div id="thioridazine.Acknowledgments"><h2 id="_thioridazine_Acknowledgments_">Acknowledgments</h2><p>The author would like to thank David Kisor, B.S., Pharm.D., Professor and Director of Pharmacogenomics Education, Pharmacogenomics Program, Manchester University, Indiana; Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of Pharmaceutical Services, Children's Cancer Hospital, Egypt; and Yolande Saab, Pharm.D., Ph.D., Associate Professor of Pharmacogenomic, School of Pharmacy, Lebanese American University, Lebanon; for reviewing this summary.</p></div><div id="thioridazine.References"><h2 id="_thioridazine_References_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="thioridazine.REF.1">THIORIDAZINE HYDROCHLORIDE- thioridazine hydrochloride tablet, film coated [packet insert]. Morgantown, WV: Mylan Pharmaceuticals, I.; 2016. Available from: <a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2479bf9f-e5ec-4bf8-b177-169107fc7763" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://dailymed<wbr style="display:inline-block"></wbr>​.nlm<wbr style="display:inline-block"></wbr>​.nih.gov/dailymed/drugInfo<wbr style="display:inline-block"></wbr>​.cfm?setid=2479bf9f-e5ec-4bf8-b177-169107fc7763</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="thioridazine.REF.2">van Os J., Kapur S. Schizophrenia. <span><span class="ref-journal">Lancet. </span>2009;<span class="ref-vol">374</span>(9690):635–45.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19700006" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19700006</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="thioridazine.REF.3">Goodnick P.J., Jerry J.M. Aripiprazole: profile on efficacy and safety. <span><span class="ref-journal">Expert Opin Pharmacother. </span>2002;<span class="ref-vol">3</span>(12):1773–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12472374" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12472374</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="thioridazine.REF.4">Yang S.Y., Kao Yang Y.H., Chong M.Y., Yang Y.H., et al. Risk of extrapyramidal syndrome in schizophrenic patients treated with antipsychotics: a population-based study. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2007;<span class="ref-vol">81</span>(4):586–94.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17235331" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17235331</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="thioridazine.REF.5">Thanacoody H.K. Thioridazine: resurrection as an antimicrobial agent? <span><span class="ref-journal">Br J Clin Pharmacol. </span>2007;<span class="ref-vol">64</span>(5):566–74.</span> [<a href="/pmc/articles/PMC2203271/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2203271</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17764469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17764469</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="thioridazine.REF.6">Fenton M., Rathbone J., Reilly J., Sultana A. Thioridazine for schizophrenia. <span><span class="ref-journal">Cochrane Database Syst Rev. </span>2007;(3):CD001944. </span> p. [<a href="/pmc/articles/PMC6718212/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6718212</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17636691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17636691</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="thioridazine.REF.7">Oshiro C., Thorn C.F., Roden D.M., Klein T.E., et al. KCNH2 pharmacogenomics summary. <span><span class="ref-journal">Pharmacogenet Genomics. </span>2010;<span class="ref-vol">20</span>(12):775–7.</span> [<a href="/pmc/articles/PMC3086352/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3086352</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20150828" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20150828</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="thioridazine.REF.8">Reilly J.G., Ayis S.A., Ferrier I.N., Jones S.J., et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. <span><span class="ref-journal">Lancet. </span>2000;<span class="ref-vol">355</span>(9209):1048–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10744090" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10744090</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="thioridazine.REF.9">Crumb W.J. Jr, Ekins S., Sarazan R.D., Wikel J.H., et al. Effects of antipsychotic drugs on I(to), I (Na), I (sus), I (K1), and hERG: QT prolongation, structure activity relationship, and network analysis. <span><span class="ref-journal">Pharm Res. </span>2006;<span class="ref-vol">23</span>(6):1133–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16715368" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16715368</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="thioridazine.REF.10">Berling I., Isbister G.K. Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram. <span><span class="ref-journal">Ann Emerg Med. </span>2015;<span class="ref-vol">66</span>(2):154–64.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25639523" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25639523</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="thioridazine.REF.11">Kongsamut S., Kang J., Chen X.L., Roehr J., et al. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. <span><span class="ref-journal">Eur J Pharmacol. </span>2002;<span class="ref-vol">450</span>(1):37–41.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12176106" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12176106</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="thioridazine.REF.12">Ray W.A., Meador K.G. Antipsychotics and sudden death: is thioridazine the only bad actor? <span><span class="ref-journal">Br J Psychiatry. </span>2002;<span class="ref-vol">180</span>:483–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12042224" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12042224</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="thioridazine.REF.13">Purhonen M., Koponen H., Tiihonen J., Tanskanen A. Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort. <span><span class="ref-journal">Pharmacoepidemiol Drug Saf. </span>2012;<span class="ref-vol">21</span>(11):1227–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22941581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22941581</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="thioridazine.REF.14">Dorado P., Penas L.E.M., de la Rubia A. -1584C>G polymorphism for thioridazine:mesoridazine plasma concentration ratio in psychiatric patients. <span><span class="ref-journal">Pharmacogenomics. </span>2009;<span class="ref-vol">10</span>(7):1083–9.</span> and L.L. A, <em>Relevance of CYP2D6</em>. p. [<a href="https://pubmed.ncbi.nlm.nih.gov/19604081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19604081</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="thioridazine.REF.15">Salih I.S., Thanacoody R.H., McKay G.A., Thomas S.H. Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2007;<span class="ref-vol">82</span>(5):548–54.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17410120" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17410120</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="thioridazine.REF.16">de Keijzer J., Mulder A., de Haas P.E., de Ru A.H., et al. Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis. <span><span class="ref-journal">J Proteome Res. </span>2016;<span class="ref-vol">15</span>(6):1776–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27068340" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27068340</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="thioridazine.REF.17">Pharmacogene Variation (PharmVar) Database [Cited Dember 14, December 2015]. Available from: <a href="https://www.pharmvar.org/gene/CYP2D6" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.pharmvar.org/gene/CYP2D6</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="thioridazine.REF.18">Kevin Hicks J., Sangkuhl K., Swen J.J., Ellingrod V.L., et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC(R)) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2016</span> [<a href="/pmc/articles/PMC5478479/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5478479</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27997040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27997040</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="thioridazine.REF.19">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*3 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816578" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816578</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="thioridazine.REF.20">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*4 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816579" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816579</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="thioridazine.REF.21">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*5 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165948092" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165948092</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="thioridazine.REF.22">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*6 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816581" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816581</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="thioridazine.REF.23">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*9 [Cited 26 Sept 2016]. Available from: <a href="https://www.pharmgkb.org/haplotype/PA165948317" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.pharmgkb<wbr style="display:inline-block"></wbr>​.org/haplotype/PA165948317</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="thioridazine.REF.24">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*10 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816582" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816582</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="thioridazine.REF.25">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*17 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816583" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816583</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="thioridazine.REF.26">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*29 [Cited 26 Sept 2016]. Available from: <a href="https://www.pharmgkb.org/haplotype/PA165948318" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.pharmgkb<wbr style="display:inline-block"></wbr>​.org/haplotype/PA165948318</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="thioridazine.REF.27">PharmGKB [Internet]. Palo Alto (CA): Stanford University. Haplotype CYP2D6*41 [Cited 8 October 2015]. Available from: <a href="http://www.pharmgkb.org/haplotype/PA165816584" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.pharmgkb.org<wbr style="display:inline-block"></wbr>​/haplotype/PA165816584</a>.</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="thioridazine.REF.28">Gaedigk A., Sangkuhl K., Whirl-Carrillo M., Klein T., et al. Prediction of CYP2D6 phenotype from genotype across world populations. <span><span class="ref-journal">Genet Med. </span>2016</span> [<a href="/pmc/articles/PMC5292679/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5292679</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27388693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27388693</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="thioridazine.REF.29">Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. <span><span class="ref-journal">Pharmacogenomics. </span>2002;<span class="ref-vol">3</span>(2):229–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11972444" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11972444</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="thioridazine.REF.30">Lerena L.A., Naranjo M.E., Rodrigues-Soares F., Penas L.E.M., et al. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. <span><span class="ref-journal">Expert Opin Drug Metab Toxicol. </span>2014;<span class="ref-vol">10</span>(11):1569–83.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25316321" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25316321</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="thioridazine.REF.31">Kannankeril P., Roden D.M., Darbar D. Drug-induced long QT syndrome. <span><span class="ref-journal">Pharmacol Rev. </span>2010;<span class="ref-vol">62</span>(4):760–81.</span> [<a href="/pmc/articles/PMC2993258/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2993258</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21079043" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21079043</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="thioridazine.REF.32">Hicks J.K., Bishop J.R., Sangkuhl K., Muller D.J., et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2015;<span class="ref-vol">98</span>(2):127–34.</span> [<a href="/pmc/articles/PMC4512908/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4512908</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25974703" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25974703</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>33.</dt><dd><div class="bk_ref" id="thioridazine.REF.33">Hicks J.K., Swen J.J., Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. <span><span class="ref-journal">Curr Drug Metab. </span>2014;<span class="ref-vol">15</span>(2):218–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24524666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24524666</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="thioridazine.REF.34">Gaedigk A., Simon S.D., Pearce R.E. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. <span><span class="ref-journal">Clin Pharmacol Ther. </span>2008;<span class="ref-vol">83</span>(2):234–42.</span> L.D. Bradford, et al. p. [<a href="https://pubmed.ncbi.nlm.nih.gov/17971818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17971818</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="thioridazine.REF.35">den Dunnen, J.T., R.
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Dalgleish, D.R.
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Maglott, R.K.
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Hart, et al. <span class="ref-title">HGVS Recommendations for the Description of Sequence Variants: 2016 Update. </span><span class="ref-journal">Hum Mutat</span>, 2016.37(6): p.564-9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/26931183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26931183</span></a>]</div></dd></dl></dl></div><h2 id="NBK424018_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>
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<sup>1</sup>
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</dt><dd><div id="thioridazine.FN1"><p class="no_top_margin"> The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.</p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK424018_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Laura Dean</span>, MD<sup>1</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> NCBI<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@naed" class="oemail">vog.hin.mln.ibcn@naed</a></div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">February 9, 2017</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a><p class="small">All Medical Genetics Summaries content, except where otherwise noted, is licensed under a Creative Commons <a href="https://creativecommons.org/licenses/by/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">Attribution 4.0 International (CC BY 4.0)</a> license which permits copying, distribution, and adaptation of the work, provided the original work is properly cited and any changes from the original work are properly indicated. Any altered, transformed, or adapted form of the work may only be distributed under the same or similar license to this one.</p></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=books" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Dean L. Thioridazine Therapy and CYP2D6 Genotypes. 2017 Feb 9. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gtrbook/thioguanine/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gtrbook/tramadol/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobthioridazineTactivitystatusofselect"><div id="thioridazine.T.activity_status_of_select" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Activity status of selected <i>CYP2D6</i> alleles</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK424018/table/thioridazine.T.activity_status_of_select/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__thioridazine.T.activity_status_of_select_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_thioridazine.T.activity_status_of_select_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Allele type</th><th id="hd_h_thioridazine.T.activity_status_of_select_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><i>CYP2D6</i> Alleles</th></tr></thead><tbody><tr><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal function</td><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*1, *2, *33, *35</i>
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</td></tr><tr><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Decreased function</td><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*9, *10, *17, *29, *41</i>
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</td></tr><tr><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No function</td><td headers="hd_h_thioridazine.T.activity_status_of_select_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*3-*8, *11-*16, *19-*21, *38, *40, *42</i>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">For a detailed list of <i>CYP2D6</i> alleles, please see (<a class="bibr" href="#thioridazine.REF.5" rid="thioridazine.REF.5">5</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobthioridazineT2016assignmentofcyp2d6"><div id="thioridazine.T.2016_assignment_of_cyp2d6" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>2016 Assignment of <i>CYP2D6</i> phenotypes by CPIC</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK424018/table/thioridazine.T.2016_assignment_of_cyp2d6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__thioridazine.T.2016_assignment_of_cyp2d6_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phenotype</th><th id="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Activity Score</th><th id="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Genotypes</th><th id="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Examples of diplotypes</th></tr></thead><tbody><tr><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYP2D6 Ultrarapid metabolizer<br />(approximately 1-20% of patients)<sup>a</sup></td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Greater than 2.0</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual carrying duplications of functional alleles</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>(*1/*1)xN<br />(*1/*2)xN<br />(*2/*2)xN</i>
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<sup>b</sup>
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</td></tr><tr><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYP2D6 Normal metabolizer<br />(approximately 72-88% of patients)</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.0 – 2.0<sup>c</sup></td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual carrying two normal function alleles <br />or two decreased function alleles <br />or one normal and no function allele <br />or one normal function and decreased function allele<br />or combinations of duplicated alleles that result in an activity score of 1.0 to 2.0</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*1/*1<br />*1/*2<br />*2/*2<br />*1/*9<br />*1/*41<br />*41/*41<br />*1/*5<br />*1/*4</i>
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</td></tr><tr><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYP2D6 Intermediate metabolizer<br />(approximately 1-13% of patients)</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual carrying one decreased function and one no function allele</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*4/*41<br />*5/*9<br />*4/*10</i>
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</td></tr><tr><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYP2D6 Poor metabolizer<br />(approximately 1-10% of patients)</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">An individual carrying two no function alleles</td><td headers="hd_h_thioridazine.T.2016_assignment_of_cyp2d6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>*4/*4<br />*4/*4xN<br />*3/*4<br />*5/*5<br />*5/*6</i>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt><sup>a</sup>
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</dt><dd><div id="thioridazine.TF.2.1"><p class="no_margin">For population-specific allele and phenotype frequencies, please see <br /><sup>b</sup> Where <i>xN</i> represents the number of <i>CYP2D6</i> gene copies (N is 2 or more).<br /><sup>c</sup> Patients with an activity core of 1.0 may be classified as intermediate metabolizers by some reference laboratories.<br />For more information about activity scores, please see the <a href="#thioridazine.Genetic_Testing">Genetic Testing</a> section.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">This table has been adapted from Hicks J.K., Sangkuhl K., Swen J.J., Ellingrod V.L., Müller D.J., Shimoda K., Bishop J.R., Kharasch E.D., Skaar T.C., Gaedigk A., Dunnenberger H.M., Klein T.E., Caudle K.E. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for <i>CYP2D6</i> and <i>CYP2C19</i> Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clinical pharmacology and therapeutics. 2016 Dec 20 [Epub ahead of print] (<a class="bibr" href="#thioridazine.REF.18" rid="thioridazine.REF.18">18</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobthioridazineTnomenclatureofselected"><div id="thioridazine.T.nomenclature_of_selected" class="table"><div class="caption"><p>Nomenclature of selected <i>CYP2D6</i> alleles</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK424018/table/thioridazine.T.nomenclature_of_selected/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__thioridazine.T.nomenclature_of_selected_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" style="text-align:left;vertical-align:top;">Common allele name</th><th id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" style="text-align:left;vertical-align:top;">Alternative names</th><th id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">HGVS reference sequence</th><th id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" style="text-align:left;vertical-align:top;">dbSNP reference identifier for allele location</th></tr><tr><th headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3" id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">Coding</th><th headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3" id="hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Protein</th></tr></thead><tbody><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*4</i>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1846G>A</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/16889/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000106.5:c.506-1G>A</a>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Variant occurs in a non-coding region (splice variant causes a frameshift)</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs3892097" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs3892097</a>
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</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*5</i>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2 hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2 hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">Variant results in a whole gene deletion</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*6</i>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1707 del T Trp152Gly<br /><p>• CYP2D6T</p></td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/16891/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000106.5:c.454delT</a>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/16891/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000097.3:p.Trp152Glyfs</a>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs5030655" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs5030655</a>
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</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*10</i>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100C>T (Pro34Ser)</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/clinvar/variation/16893/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000106.5:c.100C>T</a>
|
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/clinvar/variation/16893/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000097.3:p.Pro34Ser</a>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs1065852" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs1065852</a>
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</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*17</i>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1023C>T<sup>[1]</sup> (Thr107Ile)</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/nuccore/392513720" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_000106.5</a>:c.320C>T</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/protein/392513721/?report=GenPept" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=genpept">NP_000097.3</a>:p.Thr107Ile</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs28371706" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs28371706</a>
|
|
</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2850C>T<sup>[2]</sup> (Cys296Arg)</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/16895/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000106.5:c.886T>C</a>
|
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/clinvar/variation/16895/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000097.3:p.Cys296Arg</a>
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</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/snp/rs16947" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs16947</a>
|
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</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:top;">
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<i>CYP2D6*41</i>
|
|
</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2850C>T<sup>[2]</sup><br /><p>(Cys296Arg)</p></td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/clinvar/variation/16895/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000106.5:c.886T>C</a>
|
|
</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/clinvar/variation/16895/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000097.3:p.Cys296Arg</a>
|
|
</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/snp/rs16947" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs16947</a>
|
|
</td></tr><tr><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;">2988G>A</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/nuccore/392513720" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_000106.5</a>:c.985+39G>A</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_3 hd_h_thioridazine.T.nomenclature_of_selected_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Variant occurs in a non-coding region (impacts slicing).</td><td headers="hd_h_thioridazine.T.nomenclature_of_selected_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/snp/rs28371725" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs28371725</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>
|
|
<sup>[1]</sup>
|
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</dt><dd><div id="thioridazine.TF.e.1"><p class="no_margin">In the literature, 1023C>T is also referred to as 1111C>T, and 2850C>T is also referred to 2938C>T.</p></div></dd></dl><dl class="bkr_refwrap"><dt>
|
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<sup>[2]</sup>
|
|
</dt><dd><div id="thioridazine.TF.e.2"><p class="no_margin">In the literature, 2850C>T is also referred to as 2938C>T.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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