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Adverse Drug Reactions in Children
The problem of ADRs in children is being increasingly recognized, and they differ
from adult reactions in frequency, nature, and severity. Infants and young children,
when exposed to some drugs such as anticholinergic agents, are more likely than
adults to develop ADRs, but may also be less susceptible to toxic reactions to other
drugs. ADRs in children caused by drugs of abuse are a major problem in the
US. Children may be exposed to these drugs through in utero exposure during preg-
nancy, through breast feeding, and through exposure during adolescence. These
ADRs can include effects on the nervous system, cognitive problems, cardiovascu-
lar anomalies, and, in the case of second-hand tobacco smoke, an increased risk for
sudden infant death syndrome, acute respiratory infections, asthma, middle-ear dis-
ease, and multiple sclerosis in children.
The NIH has previously funded research that includes use of genomics, pro-
teomics, and transcriptomics technologies in the discovery and identifi cation of tox-
icity biomarkers; use of metabolomics alone or in combination with other technology
to identify and characterize novel toxicity-associated drug metabolites and unravel-
ing of novel ADR mechanisms; genomic studies that may identify animals that
develop idiosyncratic reactions similar to humans; using genomics to defi ne pat-
terns of genes association with pediatric ADRs; placental genomics, proteomics,
and biomarker identifi cation to understand ADRs; the role of epigenetic factors to
explain or predict developmental differences in the expression of ADRs; and other
studies.
Adverse Drug Reactions Related to Toxicity of Chemotherapy
Neurotoxicity and myelotoxicity are well known adverse reactions of chemother-
apy in cancer patients. Scientists at the NCI have evaluated the relationships
between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-
induced toxicity and pharmacokinetics (Sissung et al. 2006 ). Patients carrying two
reference alleles for the ABCB1 3435C > T polymorphism trended toward a reduced
risk to develop neuropathy as compared to patients carrying at least one variant
allele. Additionally, patients who were homozygous variant at the 2677 and 3435
loci had a signifi cantly greater percent decrease in absolute neutrophil count at
nadir. Neither polymorphism correlated with paclitaxel pharmacokinetics. This
pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be
linked to inherited variants of ABCB1 through a mechanism that is unrelated to
altered plasma pharmacokinetics. NCI is seeking commercial partnering to market
a test based on ABCB1 genotyping to predict toxicity of chemotherapy in individ-
ual patients.
4 Pharmacogenetics