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Wang G.S.,Aurora University | Wang G.S.,Rocky Mountain Poison and Drug Center | Levitan R.,University of Arizona | Wiegand T.J.,University of Rochester | And 3 more authors.
Journal of Medical Toxicology | Year: 2015

Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for toxicological exposure. There were 26,271 exposures (60 % female) reported to the ToxIC Registry, 10 (0.0004 %) received ECMO: 4 pediatric (< 12 years), 2 adolescent (12–18 years), and 4 adults (>18 years). Time of initiation of ECMO ranged from 4 h to 4 days, with duration from 15 h to 12 days. Exposures included carbon monoxide/smoke inhalation (2), bitter almonds, methanol, and several medications including antihistamines (2), antipsychotic/antidepressant (2), cardiovascular drugs (2), analgesics (2), sedative/hypnotics (2), and antidiabetics (2). Four ECMO patients received cardiopulmonary resuscitation (CPR) during their hospital course, and the overall survival rate was 80 %. ECMO was rarely used for poisoning exposures in the ACMT ToxIC Registry. ECMO was utilized for a variety of ages and for pharmaceutical and non-pharmaceutical exposures. In most cases, ECMO was administered prior to cardiovascular failure, and survival rate was high. If available, ECMO may be a valid treatment modality. © 2015 American College of Medical Toxicology

Gaedigk A.,Toxicology and Therapeutic Innovation | Gaedigk A.,University of Missouri - Kansas City | Garcia-Ribera C.,Autonomous University of Barcelona | Jeong H.-E.,Inje University | And 2 more authors.
Pharmacogenomics | Year: 2014

A Han Chinese patient failed CYP2D6 genotype analysis with the AmpliChip CYP450 Test™. The CYP2D6 gene locus of the patient and her son were extensively genotyped including copy number variation and gene resequencing. Two SNPs were discovered on the patient's CYP2D61 allele, -498C>A and 1661G>C, while the son's CYP2D61 allele had -498C>A only. AmpliChip failure was attributed to the presence of a CYP2D61 allele carrying the 1661G>C SNP. Functional analyses of -498C>A did not reveal altered activity in vitro or in vivo suggesting that both novel CYP2D61 subvariants are functional. The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is a reliable platform, numerous allelic (sub)variants and gene arrangements are not detected or may trigger no calls. While such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results. © 2014 Future Medicine Ltd.

De Wildt S.N.,Erasmus MC Sophia Childrens Hospital | Tibboel D.,Erasmus MC Sophia Childrens Hospital | Leeder J.S.,Toxicology and Therapeutic Innovation
Archives of Disease in Childhood: Education and Practice Edition | Year: 2014

Drug metabolism importantly determines drug concentrations. The efficacy and safety of many drugs prescribed for children are, therefore, dependent on intraindividual and interindividual variation in drugmetabolising enzyme activity. During growth and development, changes in drug-metabolising enzyme activity result in age-related differences in drug disposition, most pronounced in preterm infants and young infants. The shape of the developmental trajectory is unique to the drug-metabolising enzyme involved in the metabolism of individual drugs. Other factors impacting drug metabolism are underlying disease, drug-drug interactions and genetic variation. The interplay of age with these other factors may result in unexpected variation in drug metabolism in children of different ages. Extrapolation of adult data to guide drug dosing in children should be done with caution. The younger the child, the less reliable is the extrapolation. This review aims to identify the primary sources of variability of drug metabolism in children, the knowledge of which can ultimately guide the practitioner towards effective and safe drug therapy.

Qiao W.,Mount Sinai School of Medicine | Yang Y.,Mount Sinai School of Medicine | Sebra R.,Mount Sinai School of Medicine | Mendiratta G.,Mount Sinai School of Medicine | And 4 more authors.
Human Mutation | Year: 2016

The cytochrome P450-2D6 (CYP2D6) enzyme metabolizes ∼25% of common medications, yet homologous pseudogenes and copy number variants (CNVs) make interrogating the polymorphic CYP2D6 gene with short-read sequencing challenging. Therefore, we developed a novel long-read, full gene CYP2D6 single molecule real-time (SMRT) sequencing method using the Pacific Biosciences platform. Long-range PCR and CYP2D6 SMRT sequencing of 10 previously genotyped controls identified expected star (*) alleles, but also enabled suballele resolution, diplotype refinement, and discovery of novel alleles. Coupled with an optimized variant-calling pipeline, CYP2D6 SMRT sequencing was highly reproducible as triplicate intra- and inter-run nonreference genotype results were completely concordant. Importantly, targeted SMRT sequencing of upstream and downstream CYP2D6 gene copies characterized the duplicated allele in 15 control samples with CYP2D6 CNVs. The utility of CYP2D6 SMRT sequencing was further underscored by identifying the diplotypes of 14 samples with discordant or unclear CYP2D6 configurations from previous targeted genotyping, which again included suballele resolution, duplicated allele characterization, and discovery of a novel allele and tandem arrangement. Taken together, long-read CYP2D6 SMRT sequencing is an innovative, reproducible, and validated method for full-gene characterization, duplication allele-specific analysis, and novel allele discovery, which will likely improve CYP2D6 metabolizer phenotype prediction for both research and clinical testing applications. © 2016 Wiley Periodicals, Inc.

Brown J.T.,Toxicology and Therapeutic Innovation | Connelly M.,Childrens Mercy Kansas City | Nickols C.,University of Missouri - Kansas City | Neville K.A.,Toxicology and Therapeutic Innovation
Journal of Pediatric Ophthalmology and Strabismus | Year: 2015

Purpose: The goal of this study was to establish normative values for measurements of quantitative pupillometry in children. Methods: Quantitative pupillometry measurements were obtained from children between 1 and 18 years of age being seen for either a well child check or other outpatient appointment. Results: Maximum and minimum pupil size increased slightly with age; however, the correlation was weak (r = 0.29 and 0.19, respectively). Similarly weak correlations with age also were observed for maximum constriction velocity (r = -0.29) and dilation velocity (r = 0.27). Maximum (5.56 vs 4.97 mm) and minimum (3.74 vs 3.40 mm) pupil sizes were significantly larger in whites than in African Americans. Conclusions: Pupil size and reactivity show little correlation with age and are therefore suitable for further exploration in using pupillometry as a biomarker across the pediatric age range. Differences in race should be taken into consideration when pupillometry is used in mixed populations. © SLACK Incorporated.

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