Potential Biomarkers of Acetaminophen Injury in Children

Scientists from NCTR and the University of Arkansas for Medical Sciences have identified a panel of extracellular miRNAs with altered expression in serum and urine from human pediatric patients hospitalized with acetaminophen (APAP) overdose. The small pilot study compared the overdose group with healthy children and children receiving therapeutic APAP doses. Scientists identified four miRNAs in urine and eight miRNAs in serum with increased median levels and these also correlated with APAP protein adduct levels in serum. Additional studies with larger cohorts will be required to determine the biomarkers’ specificity and to validate potential miRNAs as APAP-specific biomarkers or biomarkers of liver injury in general. A manuscript describing the results of this study is now availableonline at Toxicology and Applied Pharmacology.

For additional information, please contact Xi Yang, Ph.D., Innovative Safety and Technologies Branch, Division of Systems Biology, FDA/NCTR.

MicroRNAs as Biomarkers of Drug Toxicity

NCTR scientists recently published a mini-review which focused on the potential of miRNAs as biomarkers of drug toxicity and explored their potential roles in both preclinical and clinical drug safety testing. The authors outlined the value of miRNAs as early and easily accessible indicators of toxicity. In addition they presented examples of potential miRNA biomarkers of toxicity in the heart, liver, brain, kidney, and skin. They also discussed the translatability of miRNA biomarkers to the human. The review is available online at Expert Opinion on Drug Metabolism and Toxicology .

For additional information, please contact Igor Pogribny, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

FDA Science Advisory Board

FDA’s Science Advisory Board (SAB) met to review the existing nonclinical and clinical data related to the use and potential toxicity of anesthetics and sedation drugs in the pediatric population on November 9, 2014. At this meeting, Dr. Merle Paule, Director of NCTR’s Division of Neurotoxicology, presented a review of the laboratory animal data published in recent years on the effects of pediatric general anesthesia. The animal data clearly show that the phenomenon of pediatric anesthetic-induced neurotoxicity (PAIN) is related to dose and duration of exposure. They also show that there are identifiable periods of sensitivity to the neurotoxic effects of exposure to general anesthetics currently in widespread use. These periods of sensitivity coincide with periods of rapid brain growth, and multiple exposures are associated with more neurotoxicity than single exposures. PAIN has been seen in species tested ranging from round worms to zebrafish to rodents to nonhuman primates. PAIN is associated with subsequent derangements in nervous-system function that manifest as diminished reflex development and cognitive dysfunction that is very long lasting or permanent.There appear to be potency differences among agents depending on the developmental period during which the exposures occur and the duration of anesthetic exposure. Studies conducted both in vitro (in cellular preparations) and in vivo (in whole animals) have identified specific biological pathways involved in the expression of PAIN and several promising mitigating strategies. The SAB offered comments to FDA with respect to further evaluations and mitigating strategies, and mechanisms to best communicate with the public regarding this issue. Dr. Paule’s talk can be viewed at: https://collaboration.fda.gov/p5wbvxvdq1l/?launcher=false&fcsContent=true&pbMode=normal.