Ketoconazole- and fluconazole-induced embryotoxicity and skeletal anomalies in wistar rats: a comparative study

Abstract

Ketoconazole and fluconazole are two broad-spectrum azole antifungals used for the treatment of superficial and systemic mycoses. Embryotoxicity and teratogenicity have been reported in some studies when those drugs are administered at high doses to pregnant rats. The aim of this study was to present a comparative study of embryotoxic effects as well as the skeletal anomalies in fetuses of Wistar rats which received ketoconazole and fluconazole at teratogenic doses on gestational days (GD) 6 through 15 (organogenesis period). On gestational day (GD) 21, the dams were euthanized and examined for standard parameters of reproductive outcome. Fetuses were stained with alizarin red and the bones of the head, trunk, forelimb and hindlimb were examined for detection of skeletal anomalies. The frequency of skeletal anomalies in the ketoconazole-treated group was significant when compared to the fluconazole and the control group.<br>O cetoconazol e o fluconazol são dois antifúngicos azólicos, de amplo espectro, utilizados no tratamento de micoses superficiais e sistêmicas. Alguns estudos relatam a embriotoxicidade e teratogenicidade induzidas por estes fármacos quando os mesmos são administrados em altas doses a ratas prenhes. O objetivo deste trabalho foi apresentar um estudo comparativo dos efeitos embriotóxicos e das anomalias esqueléticas em fetos de ratas Wistar que receberam cetoconazol e fluconazol em doses teratogênicas do 6º ao 15º dia gestacional (GD) (período da organogênese). No 21º GD as ratas foram eutanaziadas e examinadas quanto aos parâmetros padrões de performance reprodutiva. Os fetos foram corados com vermelho de alizarina e os ossos da cabeça, do tronco e dos membros anteriores e posteriores foram examinados para a verificação de anomalias esqueléticas. A freqüência de anomalias esqueléticas no grupo tratado com cetoconazol foi significante quando comparada à dos grupos fluconazol e controle

Predictive value of cell assays for developmental toxicity and embryotoxicity of conazole fungicides

“…Imbalance in RA metabolism caused by triazoles has been demonstrated both in vitro and in vivo (Marotta and tiboni, 2010). An increased level of endogenous RA was the suggested mechanism behind altered craniofacial morphogenesis such as cleft palate and reduced ossification of skull bones after in utero exposure to ketoconazole (Amaral and Nunes, 2008). Another possible mechanism for the developmental toxicity of conazole compounds might be via blocking of cardiac potassium channels.…”

Antifúngicos em infecções oculares: drogas e vias de administração

“…These drugs are metabolised primarily in the liver, therefore control of liver enzymes is recommended. They have teratogenic activity (class C) and should not be used during pregnancy (4,53) . The imidazoles used more often in ophthalmology include miconazole (MCZ), econazole (ECZ) and ketoconazole (KCZ).…”

“…Similar to KCZ, gastric absorption depends on a low pH. Studies in rats showed that ICZ has a lower teratogenic risk than KCZ (53) . Systemic administration at 400 mg/day was effective in the treatment of infections by Candida spp.…”

Ensaios preliminares em ratas wistar com extrato hidroetanólico de calunga (Simaba ferruginea St. Hil.) v.o., nas fases gestacionais de implantação, organogênese e período fetal: interferências na prole

“…No Brasil, estes estudos são regulamentados pela Agencia Nacional de Vigilância Sanitária (ANVISA), Portaria № 116/MS/SNVS, de 8 de agosto de 1996 (Brasil, 1996). A regulamentação despertou interesse em pesquisa neste assunto, e gerou vários trabalhos científicos (Moller et al, 2003;Borges et al, 2005;Brandini et al, 2005;Amaral & Nunes 2008;Camargo et al, 2009).…”