Publications by authors named "J Steven Leeder"

274 Publications

Are body surface area (BSA) based estimates of liver volume applicable to children with overweight or obesity? An in-vivo validation study.

Clin Transl Sci 2021 May 13. Epub 2021 May 13.

Children's Mercy Kansas City, Kansas City.

The liver is the primary organ responsible for clearing most drugs from the body and thus determines systemic drug concentrations over time. Drug clearance by the liver appears to be directly related to organ size. In children, organ size changes as children age and grow. Liver volume has been correlated with body surface area (BSA) in healthy children and adults and has been estimated by functions of BSA. However, these relationships were derived from "typical" populations and it is unknown whether they extend to estimations of liver volumes for population "outliers," such as children with overweight or obesity, who today represent 1/3 of the pediatric population. Using computerized tomography (CT) or magnetic resonance imaging (MRI), this study measured liver volumes in 99 children (2-21 years) with normal weight, overweight or obesity and compared organ measurements with estimates calculated using an established liver volume equation. A previously developed equation relating BSA to liver volume adequately estimates liver volumes in children, regardless of weight status.
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http://dx.doi.org/10.1111/cts.13059DOI Listing
May 2021

Recent advances in the ontogeny of drug disposition.

Br J Clin Pharmacol 2021 Mar 17. Epub 2021 Mar 17.

Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, USA.

Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult-to-interpret in vitro and in vivo animal studies. Over the last 2 decades, our understanding of the mechanistic processes underlying age-related changes in drug disposition has advanced considerably. Progress has largely been driven by technological advances in mass spectrometry-based methods for quantifying proteins implicated in drug disposition, and in silico tools that leverage these data to predict age-related changes in pharmacokinetics. This review summarizes our current understanding of the impact of childhood development on drug disposition, particularly focusing on research of the past 20 years, but also highlighting select examples of earlier foundational research. Equally important to the studies reviewed herein are the areas that we cannot currently describe due to the lack of research evidence; these gaps provide a map of drug disposition pathways for which developmental trends still need to be characterized.
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http://dx.doi.org/10.1111/bcp.14821DOI Listing
March 2021

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Clin Pharmacol Ther 2021 Jan 2. Epub 2021 Jan 2.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
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http://dx.doi.org/10.1002/cpt.2149DOI Listing
January 2021

Effect of Intrauterine Smoke Exposure on microRNA-15a Expression in Human Lung Development and Subsequent Asthma Risk.

Healthcare (Basel) 2020 Dec 4;8(4). Epub 2020 Dec 4.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

In utero smoke (IUS) exposure is associated with asthma susceptibility. We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Five miRNAs were differentially expressed across post-conception age (adjusted < 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung ( < 0.05). MiR-15a was differentially expressed by post-conception age ( = 0.00002), IUS exposure in human fetal lung ( = 0.005), and in the post-natal mouse lung ( = 0.01). MiR-15a was also associated with the in utero expression of (adjusted = 0.0002), a known childhood asthma gene and with asthma exacerbations ( = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. These results provide evidence for the role of miR-15a in the fetal origin of asthma.
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http://dx.doi.org/10.3390/healthcare8040536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761806PMC
December 2020

Sleep and the athlete: narrative review and 2021 expert consensus recommendations.

Br J Sports Med 2020 Nov 3. Epub 2020 Nov 3.

Cummings School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Elite athletes are particularly susceptible to sleep inadequacies, characterised by habitual short sleep (<7 hours/night) and poor sleep quality (eg, sleep fragmentation). Athletic performance is reduced by a night or more without sleep, but the influence on performance of partial sleep restriction over 1-3 nights, a more real-world scenario, remains unclear. Studies investigating sleep in athletes often suffer from inadequate experimental control, a lack of females and questions concerning the validity of the chosen sleep assessment tools. Research only scratches the surface on how sleep influences athlete health. Studies in the wider population show that habitually sleeping <7 hours/night increases susceptibility to respiratory infection. Fortunately, much is known about the salient risk factors for sleep inadequacy in athletes, enabling targeted interventions. For example, athlete sleep is influenced by sport-specific factors (relating to training, travel and competition) and non-sport factors (eg, female gender, stress and anxiety). This expert consensus culminates with a sleep toolbox for practitioners (eg, covering sleep education and screening) to mitigate these risk factors and optimise athlete sleep. A one-size-fits-all approach to athlete sleep recommendations (eg, 7-9 hours/night) is unlikely ideal for health and performance. We recommend an individualised approach that should consider the athlete's perceived sleep needs. Research is needed into the benefits of napping and sleep extension (eg, banking sleep).
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http://dx.doi.org/10.1136/bjsports-2020-102025DOI Listing
November 2020