Department of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America.
University of Western Australia, Perth, Australia.
PLoS One. 2019 Sep 19;14(9):e0222817. doi: 10.1371/journal.pone.0222817. eCollection 2019.
Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.
产前皮质类固醇（ACS）是有早产风险的孕妇的标准治疗方法，尽管药物选择、剂量或途径尚未得到系统评估。此外，ACS 在资源匮乏的环境中很少使用，而大多数早产儿死亡都发生在这些环境中。我们报告了原理验证实验，以测试在恒河猴模型中口服给予倍他米松磷酸酯（Beta-P）或地塞米松磷酸酯（Dex-P）与临床使用肌内组合药物 beta-磷酸酯加 beta-醋酸酯的比较。首先，我们在非妊娠猴中进行了药代动力学研究，比较了口服给予 Beta-P、Dex-P 和临床治疗中 beta-醋酸酯有效肌内剂量的类固醇的血液水平。然后，我们在超声引导下对妊娠猕猴进行了有限的胎儿采样，评估了母体和胎儿的血液类固醇水平。我们发现，与口服 Dex 相比，口服 Beta 从血浆中的清除速度较慢。与非妊娠猕猴相比，怀孕猕猴的母体血浆中两种药物的血液水平都较低。利用药代动力学数据，我们用口服 Beta-P、口服 Dex-P 或临床治疗的母体肌内治疗和盐水对照治疗 6-8 组妊娠猕猴，并测量压力-容积曲线以评估皮质类固醇对 5d 时肺成熟的影响。口服 Beta-P 使压力-容积曲线得到了类似于临床治疗的改善。口服 Dex-P 给出了更多可变且无统计学意义的反应。然后，我们通过 RNA 测序比较了口服 Beta-P 和临床治疗对胎儿肺、肝和海马中的基因表达。转录组基本相似，肺和肝中的基因表达差异较小，各组之间的海马无差异。作为原理验证，使用廉价且广泛可用的口服药物可以有效地进行 ACS 治疗。临床给药策略必须仔细考虑口服 Beta-P 或 Dex-P 的药代动力学，以在达到所需治疗反应的同时最小化胎儿暴露。
