Awodele O, Patrick E B, Oluwatoyin Agbaje Esther, Oremosu A A, Gbotolorun S C
Department of Pharmacology, College of Medicine, University of Lagos, Idi-Araba 12003, Lagos, Nigeria.
ScientificWorldJournal. 2012;2012:585094. doi: 10.1100/2012/585094. Epub 2012 May 3.
Due to the risks of disease progression and transmission to the newborn, treatment of tuberculosis is often pursued during pregnancy and fixed-dose combined antituberculous agents have been found to be beneficial. Unfortunately, there is paucity of data on the safety of the fixed-dose combined antituberculous drugs during pregnancy. This study intends to assess the teratogenic effect of fixed-dose combined antituberculous drugs on the organogenesis stage of fetal development and also investigate the possible roles of vitamin C in modulating the teratogenic effects of these agents on the fetus using animal model. Pregnant rats were divided into 3 groups with 12 animals per group: group 1 received distilled water (10 mL/kg) orally; group 2 received 51.4 mg/kg/day of fixed-dose combined antituberculous agents orally; group 3 received 51.4 mg/kg/day of fixed-dose combined antituberculous agents plus vitamin C (10 mg/kg/day) orally. Six rats in each group were randomly selected and sacrificed on day 20 by cervical dislocation prior to day 21 of gestation, and the foetuses were harvested through abdominal incision for physical examination. Blood samples were collected from the 1st filial rats of the remaining six animals for biochemical and hematological examination. The liver, kidney, heart, and brain of all the sacrificed animals were used for histopathological examination. There were significant (P ≤ 0.05) low birth weights of the foetuses of the animals that were treated with fixed-dose combined antituberculous agents. The haematological parameters also revealed a reduction in the platelets counts and neutrophiles at the first filial generation. Significant (P ≤ 0.05) elevations in the levels of aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the foetuses of the animals treated with fixed-dose combined antituberculous agents were also observed. However, the combination of vitamin C with fixed-dose combined antituberculous agents significantly (P ≤ 0.05) reduced the level of AST. Fixed-dose combined antituberculous agents have teratogenic potential as shown in low birth weight and mild liver damage in the first filial of the treated animals. As much as it is imminent to treat TB patients in pregnancy, there is need to always exercise caution and clinically weigh the risk-benefit ratio.
由于存在疾病进展和传播给新生儿的风险，孕期通常会进行结核病治疗，且已发现固定剂量联合抗结核药物有益。不幸的是，关于固定剂量联合抗结核药物在孕期安全性的数据很少。本研究旨在评估固定剂量联合抗结核药物对胎儿发育器官形成阶段的致畸作用，并使用动物模型研究维生素C在调节这些药物对胎儿致畸作用方面的可能作用。将怀孕大鼠分为3组，每组12只动物：第1组口服蒸馏水（10 mL/kg）；第2组口服51.4 mg/kg/天的固定剂量联合抗结核药物；第3组口服51.4 mg/kg/天的固定剂量联合抗结核药物加维生素C（10 mg/kg/天）。每组随机选取6只大鼠，在妊娠第21天前的第20天通过颈椎脱臼处死，通过腹部切口取出胎儿进行体格检查。从其余6只动物的第一代子代大鼠采集血样进行生化和血液学检查。所有处死动物的肝脏、肾脏、心脏和大脑用于组织病理学检查。接受固定剂量联合抗结核药物治疗的动物所产胎儿出生体重显著降低（P≤0.05）。血液学参数还显示第一代子代血小板计数和中性粒细胞减少。在接受固定剂量联合抗结核药物治疗的动物所产胎儿中，还观察到天冬氨酸转氨酶（AST）和碱性磷酸酶（ALP）水平显著升高（P≤0.05）。然而，维生素C与固定剂量联合抗结核药物联合使用显著降低了AST水平（P≤0.05）。如治疗动物第一代子代中低出生体重和轻度肝损伤所示，固定剂量联合抗结核药物具有致畸潜力。尽管在孕期治疗结核病患者迫在眉睫，但仍需始终谨慎行事，并在临床上权衡风险效益比。
