Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel.
Clinical Pharmacology & Toxicology Unit, Assaf Harofeh (Shamir) Medical Center, Beer Yakov, Israel.
Epilepsia. 2022 Nov;63(11):2949-2957. doi: 10.1111/epi.17395. Epub 2022 Sep 3.
Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus.
Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 μg/ml (10 μmol·L , n = 7) or 10 μg/ml (40 μmol·L , n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 μg/ml, 500 μmol·L , n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons.
Following a 3-h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 μg/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 μg/ml lacosamide, 83 μg/ml valproate, and 2.5 μg/ml lacosamide, respectively; p < .05).
Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.
拉科酰胺越来越多地被开给孕妇使用，但其对胎儿发育的影响尚未完全阐明。此前，我们已经表明，几种抗癫痫药物，特别是丙戊酸，可能会影响胎盘细胞中必需化合物载体的表达。在这里，我们的目的是评估人类胎盘在短时间暴露于拉科酰胺后对胎儿所需必需营养素载体表达的影响。
胎盘取自行剖宫产分娩的无癫痫病史的女性。绒毛膜从脐带中分离出来，并在存在 2.5μg/ml（10μmol·L-1，n=7）或 10μg/ml（40μmol·L-1，n=6）拉科酰胺的情况下进行 180 分钟的灌流，分别代表母体灌流中的低和高治疗浓度。丙戊酸（83μg/ml，500μmol·L-1，n=6）和灌流液（n=6）分别作为阳性和阴性对照。使用定制的基因谱芯片分析灌流绒毛中的载体基因表达。
在 3 小时的灌流后，与载体相比，用 10μg/ml 拉科酰胺处理的胎盘中 SLC19A1（编码还原叶酸载体 1）的 mRNA 表达下调（p<0.05）。在所有组中，SLC19A3（硫胺素转运体 2）的表达均有显著差异（用 10μg/ml 拉科酰胺、83μg/ml 丙戊酸和 2.5μg/ml 拉科酰胺处理后分别降低 52%、20%和 9%；p<0.05）。
高治疗浓度的拉科酰胺对人胎盘产生了药理学作用。如果这些发现能在体内表现出来，那么它们表明拉科酰胺可能会影响胎儿叶酸的供应，并支持在怀孕期间对拉科酰胺的血浆浓度进行治疗监测和谨慎调整。
