DEVELOPMENTAL TOXICITY OF CYSTEAMINE IN THE RAT - EFFECTS ON EMBRYO-FETAL DEVELOPMENT

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 add ition, there is the potential to decrease the severity or the incidenc e of renal Fanconi syndrome with administration of cysteamine to pregn ant women carrying fetuses with cystinosis, and to ease significantly the burden of this disease throughout their lives. If cysteamine incre ases significantly the risk of fetal death, growth retardation or birt h defects at doses used to treat women with cystinosis, treatment of t he affected female should cease during pregnancy and would not be cons idered for fetal treatment. The goal of this study was to assess the d evelopmental safety of exposure in utero to cysteamine in the vat. Pre gnant rats were given cysteamine (as phosphocysteamine) from day 6.5 t hrough day 18.5 postconception and fetuses were assessed for survival, growth, and structural abnormalities on day 20.5. Cysteamine was admi nistered ovally in doses of 0, 37.5, 75,100, or 150 mg/kg/day. Cysteam ine 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 m echanism for the developmental toxicity of cysteamine. (C) 1998 Wiley- Liss, Inc.