Prenatal exposure to anti-HIV drugs: Neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice

Abstract

Background The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost‐effective alternative to the current AZT monotherapy to prevent mother‐to‐fetus transmission of the HIV‐1 virus. Recent evidence in uninfected children raised concern about the long‐term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment. Methods Pregnant CD‐1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive‐avoidance testing (PND 22–23), locomotor activity (PND 23), and social interaction (PND 35). Results While no effects were observed on maternal reproductive endpoints, treated pups showed a long‐lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive‐avoidance or locomotor activity were found. AZT + 3TC‐treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions. Conclusions The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior. Teratology 63:26–37, 2001. © 2001 Wiley‐Liss, Inc.

Increased Brain Levels of F2-Isoprostane Are an Early Marker of Behavioral Sequels in a Rat Model of Global Perinatal Asphyxia

“…Homing test was carried out as described in (29). Briefly, within each litter, male pups assigned to the different experimental conditions (VD, n ϭ 12; 0-min, n ϭ 7; 10-min, n ϭ 7; 20-min, n ϭ 10) were assessed for their homing response in a Plexiglas arena (36 ϫ 22.5 ϫ 10 cm) maintained at 28 Ϯ 1°C, whose floor was subdivided into 15 quadrants.…”

“…COX-2 expression was however detected in homogenates from adult rat brains. Cortex and hippocampus regions were chosen for their constitutive expression of COX-2, which begins after the first postnatal week (29).…”

Adverse drug reactions associated with antiretroviral therapy during pregnancy

“…Adverse drug reactions in the fetus and infant exposed to ARV during intrauterine life Studies in animal models show cytotoxic activity and the occurrence of mitochondrial toxicity in embryos and fetuses exposed to NRTIs, primarily manifested by neurological and cardiac disorders [120][121][122][123][124][125][126]. In France, between 1995 and 1998, there were eight reported children who had mitochondrial dysfunction after exposure to ZDV during intrauterine life and the first weeks after birth, two of whom died [127].…”

Efeito das drogas anti-retrovirais sobre as taxas de fertilidade de ratas Wistar

“…Por sua vez, os efeitos pós-natais em fetos de ratas expostas a medicamentos anti-retrovirais no período de prenhez já estão bem estabelecidos, com amplo material presente nas principais fontes de pesquisa [20][21][22][23][24] . Dentre os parâmetros associados a fertilidade estudados, destacam-se as taxas de perdas pré e pós-implantação, taxas de eficiência de implantação e as taxas de viabilidade fetal.…”

“…Dentre os parâmetros associados a fertilidade estudados, destacam-se as taxas de perdas pré e pós-implantação, taxas de eficiência de implantação e as taxas de viabilidade fetal. Inúme-ros estudos apresentam resultados com alterações diversas nesses índices, com os mais diversos tipos de drogas, dentre eles alguns antiretrovirais [12][13][14][15][16][20][21][22][23][24] . Como visto, existem lacunas no conhecimento do efeito das drogas anti-retrovirais sobre as taxas de fertilidade em animais e, até o presente, modelos experimentais para avaliar o efeito desses fármacos sobre as taxas reprodutivas em ratos durante a prenhez ainda não foram amplamente testados.…”