Clinical Pharmacology and Pharmacokinetics, Lundbeck Inc., Four Parkway North, Deerfield, IL 60015, USA.
Neurotoxicology. 2011 Dec;32(6):963-74. doi: 10.1016/j.neuro.2011.03.014. Epub 2011 Apr 5.
Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1.
During Study 1, immature Sprague Dawley rats were orally administered deionized water (vehicle control), or vigabatrin at 5, 15, or 50mg/kg/day for ≤ 9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50mg/kg/day for ≤ 9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME.
At 5-50mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50mg/kg/day, and were attenuated during recovery. Vacuolar-change morphology was characteristic of IME, with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4-15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4-46 and 4-65. Vacuolation was markedly attenuated in post-recovery-period rats.
The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages <50mg/kg/day did not affect CNS, behavior, and reproductive development. However, at the greatest dosage, some retardation of physical growth, delay in sexual maturation, reduction in physical strength, and induction of CNS stimulation (handling-induced spasms) occurred. The key pathologic finding was vacuolar brain lesions in the white and gray matter, which generally reversed upon drug discontinuation. Vacuoles were confined to myelin sheaths, consistent with observations in adult rats. Vigabatrin delayed but did not eliminate myelination despite continued dosing, an effect greatest during active myelination.
对发育不成熟的 Sprague Dawley 大鼠进行 vigabatrin 的两项毒理学研究，以描述髓鞘内水肿（IME）的形成，并评估其对行为测量的潜在影响。研究 1 是 vigabatrin 在年轻发育中的大鼠中的总体毒性的剂量范围特征描述。研究 2 评估了研究 1 中发现的空泡性脑病变。
在研究 1 期间，将发育不成熟的 Sprague Dawley 大鼠经口给予去离子水（载体对照）或 vigabatrin，剂量为 5、15 或 50mg/kg/天，持续≤9 周，从出生后第 4 天（PND 4）开始，并随后进行恢复期。收集毒理学观察结果，包括不良临床体征、体重增加、食物消耗、眼科学、视网膜电图、性成熟、运动活动、记忆和学习行为。在牺牲时，通过光镜检查中枢神经系统组织是否存在 IME。在研究 2 中，再次将发育不成熟的 Sprague Dawley 大鼠经口给予 vigabatrin（50mg/kg/天，持续≤9 周，从 PND 4 开始）。在牺牲时，通过光镜和透射电镜检查中枢神经系统组织是否存在 IME。
在 5-50mg/kg/天的剂量范围内，发现与剂量相关的食物摄入量减少、体重减轻和性成熟延迟。在恢复期，这些影响在雄性中更为明显。仅在 50mg/kg/天的剂量下，在 PND 67 时观察到更严重的空泡化程度，并在恢复期减弱。空泡化改变的形态特征为 IME，没有细胞或神经突变性的证据。超微结构分析显示，脑空泡是沿内周期线髓鞘分裂开始的。这些分裂扩大，发展成富含膜的大空泡，在髓鞘发育的后期更为明显。从 PND 4-15 观察到少突胶质细胞病变和神经胶质病，这可能与 vigabatrin 在活跃髓鞘形成期间的暴露有关。从 PND 4-46 和 PND 4-65 观察到较少程度的少突胶质细胞病变。在恢复期后，空泡化明显减轻。
本研究表明，在年轻大鼠中，vigabatrin 的毒性剂量低于在老年大鼠中报告的毒性剂量。<50mg/kg/天的剂量不会影响中枢神经系统、行为和生殖发育。然而，在最大剂量下，会出现一些身体生长迟缓、性成熟延迟、体力下降和中枢神经系统刺激（处理引起的痉挛）。关键的病理发现是白质和灰质中的空泡性脑病变，停药后通常会逆转。空泡仅限于髓鞘，与成年大鼠的观察结果一致。尽管持续给药，但 vigabatrin 延迟而不是消除髓鞘形成，在活跃的髓鞘形成期间影响最大。
