Drug-induced seizures in children and adolescents presenting for emergency care: current and emerging trends.

CONTEXT: Seizures may be the presenting manifestation of acute poisoning in children. Knowledge of the etiologic agent, or likely drug-class exposure, is crucial to minimize morbidity and optimize care. OBJECTIVES: To describe the agents most commonly responsible for pediatric drug-induced seizures, whose evaluation included a medical toxicology consultation in the United States. METHODS: Using the 37 participating sites of the Toxicology Investigators Consortium (ToxIC) Case Registry, a cross-country surveillance tool, we conducted an observational study of a prospectively collected cohort. We identified all pediatric (younger than 18 years) reports originating from an Emergency Department (ED) which included a chemical or drug-induced seizure, and required a medical toxicology consultation between April 1, 2010 and March 31, 2012. Results. We identified 142 pediatric drug-induced seizure cases (56% male), which represent nearly 5% of pediatric cases requiring bedside consultation by medical toxicologists. One-hundred and seven cases (75%) occurred in children aged 13-18 years, and 86 (61%) resulted from intentional ingestions. Antidepressants were the most commonly identified agents ingested (n = 61; 42%), of which bupropion was the leading drug (n = 30; 50% of antidepressants), followed by anticholinergics/antihistamines (n = 31; 22%). All antidepressant-induced seizures in teenagers were intentional and represented self-harm behavior. Sympathomimetic agents, including street drugs, represent the most common agents in children younger than 2 years (n = 4/19). CONCLUSION: Antidepressants, and specifically bupropion, are presently the most common medications responsible for pediatric drug-induced seizures requiring medical toxicology consultation in the United States. In teenagers presenting with new-onset seizures of unknown etiology, the possibility of deliberate self-poisoning should be explored, since most drug-induced seizures in this age group resulted from intentional ingestion.

Adverse placental effect of formic acid on hCG secretion is mitigated by folic acid.

AIMS: Formic acid has recently been detected in maternal blood and umbilical cord blood of infants born to alcohol abusing mothers. This toxic metabolite of methanol requires folate for detoxification. We hypothesized that formic acid produced in the maternal circulation will transfer across the placenta and will be toxic to the placenta. Our objectives were, first, to determine whether formic acid transfers across the human placenta and whether it is toxic to the placenta and second, to determine whether folate can decrease transplacental transfer of formic acid and mitigate toxicity. METHODS: Dual perfusion of a single placental lobule ex vivo was used to characterize the transfer of formic acid across the placenta. After a 1-h control period, formic acid (2 mM) was introduced into the maternal circulation with (n = 4) or without folate (1 µM) (n = 4) and was allowed to equilibrate for 3 h. RESULTS: Formic acid transferred rapidly from the maternal to the fetal circulation, and transfer was not altered with the addition of folate. Compared with the control period, there was a significant decrease in hCG secretion (P = 0.03) after addition of formic acid. The addition of folic acid to the perfusate mitigated the decrease in hCG. CONCLUSIONS: Formic acid rapidly transfers across the placenta and thus has the potential to be toxic to the developing fetus. Formic acid decreases hCG secretion in the placenta, which may alter steroidogenesis and differentiation of the cytotrophoblasts, and this adverse effect can be mitigated by folate.

The fetal safety of thiopurines for the treatment of inflammatory bowel disease in pregnancy.

Maintaining remission of inflammatory bowel disease (IBD) during pregnancy is critical for positive pregnancy outcomes. Conflicting data exist regarding the association between thiopurine use for IBD treatment in pregnancy and adverse pregnancy outcomes and this meta-analysis aims to clarify this association. A meta-analysis was performed of all original human studies reporting outcomes in pregnancy in patients receiving thiopurines. Nine studies satisfied the inclusion criteria and a total of 494 patients with IBD and 2,782 IBD controls were reported. When compared with healthy women, those receiving thiopurines had an increased risk for congenital malformations (RR 1.45; 95% CI 1.07-1.96; p = 0.02); however, when compared with IBD controls, there was no increased risk (RR 1.37; 95% CI 0.92-2.05; p = 0.1). These data provide support for thiopurines having a minimal risk, if any, to the fetus.

The transfer of 6-mercaptopurine in the dually perfused human placenta.

The immunosuppressant azathioprine is increasingly being used in pregnancy. The human placenta is considered a relative barrier to the major metabolite, 6-mercaptopurine (6-MP), and likely explains the lack of proven teratogenicity in humans. The aim of this study was to determine how the human placenta restricts 6-MP transfer using the human placental perfusion model. After addition of 50 ng/ml (n=4) and 500 ng/ml (n=3) 6-MP into the maternal circulation, there was a biphasic decline in its concentration and a delay in fetal circulation appearance. Under equilibrative conditions, the fetal-to-maternal concentration ratio was >1.0 as a result of ion trapping. Binding to placental tissue and maternal pharmacokinetic parameters are the main factors that restrict placental transfer of 6-MP. Active transport is unlikely to play a significant role and drug interactions involving, or polymorphisms in, placental drug efflux transporters are not likely to put the fetus at risk of higher 6-MP exposure.

The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs.

Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. To date, there has not been any attempt at a systematic evaluation of this model. The aim of this study was to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a pharmacokinetic model to account for nonplacental pharmacokinetic parameters in the perfusion results. In general, the fetal-to-maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery of the infant. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R² = 0.85, P < 0.0001). Placental perfusion experiments can be used to predict placental drug transfer when adjusting for extra parameters and can be useful for assessing drug therapy risks and benefits in pregnancy.

Placental P-glycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology.

Recent studies have illustrated the importance of placental drug transport proteins, such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in limiting fetal exposure to drugs and toxins. Moreover, increasing evidence supports a role for Pgp and BCRP in the normal development and physiological function of the placenta. Several single nucleotide polymorphisms (SNPs) in the genes encoding Pgp and BCRP have been described and are associated with altered protein expression, transporter activity, and clinical outcome in studies focusing on tissues other than the placenta. This review aims to summarize current research regarding the association between these polymorphisms and expression and function in the placenta. The influence of these genotypes on fetal drug exposure and altered placental physiology or development is also presented. To date, evidence suggests that SNPs in both ABCB1 and ABCG1 can alter expression of their respective protein; however, the functional significance of these polymorphisms is less clear. An understanding of this genotype-phenotype relationship will allow for prediction of susceptible or favorable genotypes in order to personalize medication choices to minimize fetal exposure to teratogens, or to maximize pharmacological therapy to the fetus.

Detection and quantification of fatty acid ethyl esters in meconium by headspace-solid-phase microextraction and gas chromatography-mass spectrometry.

Meconium fatty acid ethyl esters (FAEEs) are currently used as biomarkers to detect heavy prenatal alcohol exposure. We introduce a novel technique to quantify FAEEs in meconium using headspace-solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS). This method improves on previous approaches by decreasing sample preparation time, eliminating the need for organic solvents, and reducing the required sample size. Using 50mg of meconium, the detection limits of FAEEs ranged from 0.05 to 0.16 nmol/g and had good reproducibility making it ideal for routine analysis of clinical samples.