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

Section of Comparative Psychology, Laboratorio di Fisiopatologia O. S., Istituto Superiore di Sanità (I.S.S.), 00161 Rome, Italy.
Teratology 01/2001; 63(1):26-37. DOI: 10.1002/1096-9926(200101)63:1<26::AID-TERA1005>3.0.CO;2-G
Source: PubMed


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.
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).
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.
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.

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    • "Pups were then assessed for a number of measures currently used in the study of sensorimotor ontogeny in mice according to a slightly modified Fox battery [25,29,45]. The tests were conducted during the dark period between 09:00 and 14:00 hr under red light, each subject being tested at approximately the same time of the day. "
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    Environmental Health 04/2009; 8(1):12. DOI:10.1186/1476-069X-8-12 · 3.37 Impact Factor
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    • "The homing test was performed as previously described (Venerosi et al., 2001). On P11, the mice were tested inside a standard mouse cage in which 1/3 of the cage was evenly filled with shavings from the home cage and the remaining 2/3 of the cage with clean shavings. "
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    ABSTRACT: A avaliação dos agentes anti-retrovirais utilizando modelos experimentais permite testar os efeitos farmacológicos e adversos destes fármacos sobre o organismo matemo e fetal. O objetivo do presente estudo foi avaliar experimentalmente os efeitos de drogas anti-retrovirais isoladas e em associação sobre as taxas de fertilidade em ratas prenhes expostas a estes fármacos, bem como o efeito perinatal nas crias. O estudo foi realizado no Biotério do Departamento de Clínica Médica da FMRP-USP, utilizando ratas fêmeas prenhes adultas da raça Wistar, pesando entre 200 e 230g. As drogas utilizadas nos experimentos foram a azidotimidina (AZT), lamivudina (3TC) e nelfinavir (NFV), com as dosagens respectivas de 25 mg, 12,5 mg e 97,5 mgidia, administradas isoladamente ou em associação. No total foram avaliados sete grupos, incluindo o controle. O inicio da experimentação foi o dia zero da prenhez de todos os animais, independente do grupo. A forma de sacrificio dos animais foi por decapitação após 7, 14 e 21 dias de prenhez, seguida das etapas experimentais descritas. A cesariana foi realizada imediatamente após a decapitação do animal. Uma vez aberto o útero, foram contados os fetos vivos e mortos, os quais foram retirados para anotação do sexo, pesagem dos fetos vivos e respectivas placentas. Em seguida, os cornos uterinos foram dissecados e, por observação direta, anotada a presença de reabsorções precoces e tardias (abortamentos). O número de sít. ... (continuação) 0,05. Conclusões: não houve alterações significativas nas taxas de perdas pré-implantação e da eficiência de implantação de ratas tratadas com anti-retrovirais isolados e em associação. Houve aumento significativo nas taxas de perda pós-implantação nos grupos de ratas tratadas com anti-retrovirais isolados e em associação. Observou-se também, redução significativa nas taxas de viabilidade fetal e número de fetos por ninhada nos animais que receberam as drogas isoladamente e associadas e houve redução do peso matemo e dos fetos nos grupos tratados com 3TC, AZT+3TC e AZT+3TC+NFV. Apesar de experimental, este estudo sinaliza para a necessidade de se pesquisar outros fármacos anti-retrovirais com menor potencial histotóxico e que possam, com segurança, serem utilizados por gestantes portadoras da infecção pelo vírus da imunodeficiência humana. Dissertação (Mestrado).
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