Neuro-immuno-teratogenicity of drugs used in neonatal pharmacotherapy in relation to the ontogenic stage at the time of their administration.
The risk of functional teratogenicity of two drugs used in neonatal pharmacotherapy was studied: indomethacin (INDO) and dexamethasone (DEX). Model experiments were carried out in Wistar strain rats, breed Konárovice, which received single subcutaneous drug injection (INDO 2 mg/kg, DEX 1 mg/kg) on postnatal day 4 (PD:4; model of human fetus/preterm newborn of 6-7-month-gestational age) or on postnatal day 9 (PD:9; model of full-term human neonate). The rats were followed up during development (body weight, maturation) till late adulthood (age 6-8 months) using tests of cognition, immune reactivity and biochemical brain analysis. The results evaluated by comparing treated and control litter-mates indicated that the functional teratogenic risk was significantly higher in DEX than in INDO. DEX-rats revealed disorganization of developmental processes: retardation of body growth, but acceleration of sensory development (pinna and eye opening), retarded male sexual maturation. Adult DEX-rats (age 6 months) of both series (PD:4, PD:9) had deficit of short-term memory (social recognition test). Disturbances of immune reactivity (decrease of humoral and rise of cell-mediated immune response) appeared both in adult INDO and DEX-rats (age 7 months), but only in the PD:9 series i.e. when the drugs were administered at a higher stage of the ontogenic development simulating neonatal period in humans. This finding may be warning from the clinical point of view for the neonatological practice.
Benesová
O
O
Prague Psychiatric Center, Prague, Czech Republic. benesova@pcp.lf3.cuni.cz
Tejkalová
H
H
Kristofiková
Z
Z
Panajotova
V
V
Husek
P
P
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D000917:Antibody Formation / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D003907:Dexamethasone / Q000633:toxicity*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007213:Indomethacin / Q000633:toxicity*; D007231:Infant, Newborn; D008297:Male; D008568:Memory / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012919:Social Behavior; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D003907:Dexamethasone; D007213:Indomethacin