Beckman D A, Mullin J J, Assadi F K
Division of Developmental Biology, Nemours Research Programs, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA.
Teratology. 1998 Sep-Oct;58(3-4):96-102. doi: 10.1002/(SICI)1096-9926(199809/10)58:3/4<96::AID-TERA5>3.0.CO;2-7.
The reproductive and developmental safety of cysteamine has become an important issue to children with cystinosis because renal transplants and treatment with cysteamine reduce the complications associated with cystinosis and increase the lifespan of the affected children. In addition, there is the potential to decrease the severity or the incidence of renal Fanconi syndrome with administration of cysteamine to pregnant women carrying fetuses with cystinosis, and to ease significantly the burden of this disease throughout their lives. If cysteamine increases significantly the risk of fetal death, growth retardation or birth defects at doses used to treat women with cystinosis, treatment of the affected female should cease during pregnancy and would not be considered for fetal treatment. The goal of this study was to assess the developmental safety of exposure in utero to cysteamine in the rat. Pregnant rats were given cysteamine (as phosphocysteamine) from day 6.5 through day 18.5 postconception and fetuses were assessed for survival, growth, and structural abnormalities on day 20.5. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. Cysteamine produced dose-dependent developmental toxicity with an apparent no adverse effect observed level of 75 mg/kg/day. Specific malformations were associated with this effect (cleft palate, kyphosis), as well as intrauterine growth retardation and fetal death at 100-150 mg/kg/day, without signs of maternal toxicity. Investigations continue into the mechanism for the developmental toxicity of cysteamine.
半胱胺的生殖与发育安全性已成为患有胱氨酸病儿童的一个重要问题，因为肾移植和半胱胺治疗可减少与胱氨酸病相关的并发症，并延长患病儿童的寿命。此外，对怀有患胱氨酸病胎儿的孕妇施用半胱胺，有可能降低肾性范科尼综合征的严重程度或发病率，并显著减轻其一生的疾病负担。如果半胱胺在用于治疗患胱氨酸病女性的剂量下显著增加胎儿死亡、生长迟缓或出生缺陷的风险，那么患病女性在孕期应停止治疗，且不应考虑对胎儿进行治疗。本研究的目的是评估大鼠子宫内接触半胱胺的发育安全性。在受孕后第6.5天至第18.5天，给怀孕大鼠施用半胱胺（以磷酸半胱胺形式），并在第20.5天评估胎儿的存活、生长及结构异常情况。半胱胺的口服剂量为0、37.5、75、100或150毫克/千克/天。半胱胺产生剂量依赖性发育毒性，观察到的明显无不良反应水平为75毫克/千克/天。这种效应伴有特定的畸形（腭裂、脊柱后凸），以及在100 - 150毫克/千克/天剂量下出现的子宫内生长迟缓及胎儿死亡，且无母体毒性迹象。关于半胱胺发育毒性机制的研究仍在继续。
