Mary Jayne Kennedy

The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an “activity score” (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African‐American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.

Hormonal Regulation of Hepatic Drug‐Metabolizing Enzyme Activity During Adolescence

Activities of drug‐metabolizing enzymes (DMEs) are known to change throughout the course of physical and sexual maturation, with the greatest variability noted during infancy and adolescence. The mechanisms responsible for developmental regulation of DME are currently unknown. However, the hormonal changes associated with puberty/adolescence provide a theoretical framework for understanding the biochemical regulation of DME activity during growth and maturation. Important information regarding potential influences of growth and sex hormones can also be extrapolated from studies that evaluate changes in activities of DMEs occurring as a consequence of physiological, pathological, and/or pharmacological hormonal fluctuations. Collectively, current data support the hypothesis that isoform‐specific alterations in DME activity during adolescence are mediated by sex and/or growth hormones. Characterization of the underlying biochemical alterations responsible for developmental changes in DME activity will require additional studies in which relationships between DMEs and important hormonal axes are evaluated during the course of pubertal development.

Association of the histamine N-methyltransferase C314T (Thr105Ile) polymorphism with atopic dermatitis in Caucasian children.

Study Objective. To investigate potential associations between the histamine N‐methyltransferase (HNMT) gene, HNMT, C314T (Thr105Ile) polymorphism and atopic dermatitis in a cohort of Caucasian children.

The essential research curriculum for doctor of pharmacy degree programs.

In 2008, the American College of Clinical Pharmacy appointed the Task Force on Research in the Professional Curriculum to review and make recommendations on the essential research curriculum that should be part of doctor of pharmacy (Pharm.D.) degree programs. The essential research curriculum provides all students with critical and analytical thinking and lifelong learning skills, which will apply to current and future practice and stimulate some students to pursue a career in this field. Eight key curricular competencies are as follows: identifying relevant problems and gaps in pharmaco‐therapeutic knowledge; generating a research hypothesis; designing a study to test the hypothesis; analyzing data results using appropriate statistical tests; interpreting and applying the results of a research study to practice; effectively communicating research and clinical findings to pharmacy, medical, and basic science audiences; interpreting and effectively communicating research and clinical findings to patients and caregivers; and applying regulatory and ethical principles when conducting research or using research results. Faculty are encouraged to use research‐related examples across the curriculum in nonresearch courses and to employ interactive teaching methods to promote student engagement. Examples of successful strategies used by Pharm.D. degree programs to integrate research content into the curriculum are provided. Current pharmacy school curricula allow variable amounts of time for instructional content in research, which may or may not include hands‐on experiences for students to develop research‐related skills. Therefore, an important opportunity exists for schools to incorporate the essential research curriculum. Despite the challenges of implementing these recommendations, the essential research curriculum will position pharmacy school graduates to understand the importance of research and its applications to practice. This perspective is provided as an aid and a challenge to those in leadership and teaching positions within schools and colleges of pharmacy.

Inflammation and Cystic Fibrosis Pulmonary Disease

Inflammation plays a primary role in the pathogenesis of cystic fibrosis (CF)‐related lung disease. Controlling the inflammatory process with antiinflammatory therapy may slow the progression of pulmonary disease and thereby decrease morbidity. Despite potential benefits of antiinflammatory therapy, both the decision to treat and selection of the most appropriate therapeutic agent are controversial. Although oral corticosteroids are associated with reduced progression of pulmonary disease, the risk of clinically significant adverse effects limits long‐term therapy. Clinical studies with inhaled corticosteroids failed to report positive effects on reducing airway inflammation. Based on available clinical data, routine therapy with these agents should be limited to patients with asthma or steroid‐responsive wheezing. High‐dosage ibuprofen has a beneficial effect on reducing the annual rate of decline in pulmonary function in patients with mild lung disease. Whereas initial results are encouraging, they do not support routine ibuprofen therapy in all patients with CF. However, as advocated by the Cystic Fibrosis Foundation, high‐dosage ibuprofen may be considered in children 5–12 years of age with a baseline forced expiratory volume of 60% predicted or greater.

Identification and Characterization of CYP2D6*56B, an Allele Associated with the Poor Metabolizer Phenotype

A 5‐year‐old African‐American girl presented with a CYP2D6*4xN/*10 genotype that was discordant with her poor metabolizer phenotype determined with the probe drug dextromethorphan. Both phenotype and genotype were confirmed in repeat assessments, suggesting that the CYP2D6*10 allele carried a novel debilitating sequence variation(s). The rationale for this study was to resolve the discordance and to describe the novel non‐functional allelic variant of CYP2D6 and its frequency in populations of different ethnic backgrounds.

Activities of Cytochrome P450 1A2, N‐acetyltransferase 2, Xanthine oxidase, and Cytochrome P450 2D6 are Unaltered in Children with Cystic Fibrosis

The activities of hepatic cytochrome P450 (CYP) 1A2, N‐acetyltransferase 2 (NAT‐2), xanthine oxidase (XO), and CYP2D6 were evaluated in 12 young children (aged 3–8 years) with mild cystic fibrosis (CF) and 12 age‐matched healthy control subjects by use of standard caffeine and dextromethorphan phenotyping methods. Subjects were given 4 oz of Coca‐Cola (approximately 35 mg caffeine) (The Coca‐Cola Company, Atlanta, Ga) and a single 0.5‐mg/kg dose of dextromethorphan. Urine was collected for 8 hours after biomarker administration, and enzyme activity was assessed by use of previously validated caffeine and dextromethorphan molar ratios. CYP2D6 genotyping was also performed in 10 of 12 subjects with CF and 11 of 12 control subjects. There were no significant differences in the urinary molar ratios for any of the enzyme systems evaluated. These data suggest that CF does not alter the activities of CYP1A2, NAT‐2, XO, and CYP2D6. Altered biotransformation of drugs in this patient population is likely enzyme‐ and isoform‐specific and thus is apparent for only selected compounds that are substrates for enzymes other than CYP1A2, NAT‐2, XO, and CYP2D6.

Comparison of Various Urine Collection Intervals for Caffeine and Dextromethorphan Phenotyping in Children

Caffeine and dextromethorphan have been used successfully both alone and in combination to assess phenotype and enzyme activity in children of various ages. Previous pediatric phenotyping studies with these agents have used varying durations of urine collection. However, the minimum duration required for accurate phenotypic assessment with these compounds in children remains unknown. We calculated the cumulative metabolite recoveries and molar ratios in urine collected from children for 2, 4, 6, and 8 hours after caffeine and dextromethorphan administration to determine when respective urinary molar ratios stabilize and thus likely accurately reflect enzyme activity. Subjects (n = 24, ages 3–8 years) were given 4 oz of Coca‐Cola®(∼11.5 mg caffeine) and a single oral dose of dextromethorphan (0.5 mg/kg). Urine was collected at discrete intervals (0–2, 2–4, 4–6, and 6–8 h) during an 8‐hour period, and the cumulative metabolite recoveries and urinary molar ratios were calculated. CYP2D6 genotyping was also performed in 21 of 24 subjects. In CYP2D6 extensive metabolizers, the extent of recovery for relevant metabolites was equivalent by 4 hours and represented 45% to 60% of the total amount recovered in the 8‐hour period. The 2‐hour CYP1A2 ratio was significantly different from those of longer collection intervals. Metabolite ratios for all other enzymes (i.e., NAT‐2, XO, and CYP2D6) were independent of the duration of urine collection. These data suggest that a 4‐hour urine collection is adequate for the concurrent assessment of hepatic CYP1A2, NAT‐2, XO, and CYP2D6 activity in children ages 3 to 8 years who are CYP2D6 extensive metabolizers, using standard caffeine and dextromethorphan phenotyping methods. Longer collection periods may be required, however, in younger children or CYP2D6 poor metabolizers.

Resuscitation Practices Associated With Survival After In-Hospital Cardiac Arrest: A Nationwide Survey

IMPORTANCE Although survival of patients with in-hospital cardiac arrest varies markedly among hospitals, specific resuscitation practices that distinguish sites with higher cardiac arrest survival rates remain unknown. OBJECTIVE To identify resuscitation practices associated with higher rates of in-hospital cardiac arrest survival. DESIGN, SETTING, AND PARTICIPANTS Nationwide survey of resuscitation practices at hospitals participating in the Get With the Guidelines-Resuscitation registry and with 20 or more adult in-hospital cardiac arrest cases from January 1, 2012, through December 31, 2013. Data analysis was performed from June 10 to December 22, 2015. MAIN OUTCOMES AND MEASURES Risk-standardized survival rates for cardiac arrest were calculated at each hospital and were then used to categorize hospitals into quintiles of performance. The association between resuscitation practices and quintiles of survival was evaluated using hierarchical proportional odds logistic regression models. RESULTS Overall, 150 (78.1%) of 192 eligible hospitals completed the study survey, and 131 facilities with 20 or more adult in-hospital cardiac arrest cases comprised the final study cohort. Risk-standardized survival rates after in-hospital cardiac arrest varied substantially (median, 23.7%; range, 9.2%-37.5%). Several resuscitation practices were associated with survival on bivariate analysis, although only 3 were significant after multivariable adjustment: monitoring for interruptions in chest compressions (adjusted odds ratio [OR] for being in a higher survival quintile category, 2.71; 95% CI, 1.24-5.93; P = .01), reviewing cardiac arrest cases monthly (adjusted OR for being in a higher survival quintile category, 8.55; 95% CI, 1.79-40.00) or quarterly (OR, 6.85; 95% CI, 1.49-31.30; P = .03), and adequate resuscitation training (adjusted OR, 3.23; 95% CI, 1.21-8.33; P = .02). CONCLUSIONS AND RELEVANCE Using survey information from acute care hospitals participating in a national quality improvement registry, we identified 3 resuscitation strategies associated with higher hospital rates of survival for patients with in-hospital cardiac arrest. These strategies can form the foundation for best practices for resuscitation care at hospitals given the high incidence and variation in survival for in-hospital cardiac arrest.

Delayed Diagnosis of Penicillin-resistant Streptococcus mitis Endocarditis Following Single-Dose Amoxicillin Prophylaxis in a Child

Children with certain underlying cardiac conditions (e.g., complex cyanotic congenital heart disease, patent ductus arteriosus [PDA], ventricular septal defect [VSD], atrial septal defect [ASD]) are at increased risk for developing infective endocarditis following dental procedures.1 Given the subacute and relatively uncommon nature of the disease, however, it is not unusual for the symptoms of endocarditis to be mistaken for those of other, more common, diagnoses, part icularly in those children treated with antimicrobial prophylaxis. Consequently, diagnosis of endocarditis in at-risk children is frequently delayed, resulting in administration of potentially inappropriate antibiotics and increased morbidity. Although recommended by the American Heart Association (AHA),1 protective efficacy of antimicrobial prophylaxis has never been definitively proven. Cases of apparent treatment failure, the mechanisms of which remain unclear, also continue to be reported among patients receiving prophylactic therapy.2,3 We describe a case of a symptomatic child in whom diagnosis of endocarditis was significantly delayed following antimicrobial prophylaxis. We also discuss factors (i.e., resistance, suboptimal antimicrobial exposure) that might have contributed to apparent treatment failure.