THE POSSIBLE TERATOGENIC EFFECTS OF KETOCONAZOLE IN ALBINO RAT FETUSES
Gamal Hosney Mohamed
Department of Anatomy and Embryology Faculty of Medicine, Cairo University
Background: Ketoconazole (imidazole-derivatives) plays a key role as antifungal in agriculture and in human mycoses. Antifungal agents are extensively used in human medicine. Therefore, their reproductive toxicological effects need to be ascertained both in terms of maternal exposure and reproductive outcome.
Aim of the work: The aim of the present study is to identify the possible teratogenic effects of Ketoconazole on craniofacial development of the rat embryo and to evaluate this effect in relation to different doses of Ketoconazole.
Material and Methods: In this work forty pregnant albino rats were used. The pregnant albino rats were divided into three groups. Group I: consisted of ten pregnant rats and used as control group that received nothing. Group II: consisted of ten pregnant rats used as sham control group, this group received normal saline intraperitoneal. Group III: consisted of twenty pregnant rats and will be further subdivided into two equal subgroups, ten rats each. Subgroup IIIA: Rat received 40 mg/kg/day of Ketoconazole intraperitoneal. Subgroup IIIB: Rats received 80 mg/kg/day Ketoconazole intraperitoneal during the period of organogenesis.
Results: In this study the pregnant rats of group I yielded 80 implantation sites with 6 resorptions, 73 living fetuses and 1 dead fetus. Group II yielded 90 implantation sites with 7 resorptions, 81 living fetuses and 2 dead fetuses. The pregnant rats of group III A yielded 100 implantation sites with 30 resorptions, 60 living fetuses and 10 dead fetuses. The pregnant rats of Group III B yielded 100 implantation sites with 40 resorptions, 45 living fetuses and 15 dead fetuses. All fetuses were examined for external abnormalities, then half of the fetuses were examined by free hand razor blade sectioning and the other half was examined for fetal skeletal defects after staining with Alizarin red. our Study with Ketoconazole have established that gestational age at days 6-15 is a sensitive embryonic period in the albino rat for inducing craniofacial defects. The administration of Ketoconazole in high doses to pregnant rats resulted in high degree of fetal resorptions, stillbirth and low birth weight. The rats exposed to Ketoconazole prenatally showed macroglossia, nasal conches hypertrophy, microphthalmia and macrophthalmia with reduce or absent ossification in skull bones.
Conclusion: Ketoconazole has teratogenic effect in craniofacial region. our Study with Ketoconazole have established that gestational age at days 6-15 is a sensitive embryonic period in the rat for inducing craniofacial defects. So it should be given in great caution during pregnancy to avoid its hazardous effect.