title: Oral toxicity of vigabatrin in immature rats: characterization of intramyelinic edema.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacology and Pharmacokinetics, Lundbeck Inc., Four Parkway North, Deerfield, IL 60015, USA. mwalzer@gmail.com
authors.forename: Mark
authors.initials: M
authors.lastname: Walzer
authors.forename: Ihor
authors.initials: I
authors.lastname: Bekersky
authors.forename: Stephen
authors.initials: S
authors.lastname: Wanaski
authors.forename: Stephen
authors.initials: S
authors.lastname: Collins
authors.forename: Bernard
authors.initials: B
authors.lastname: Jortner
authors.forename: Reid
authors.initials: R
authors.lastname: Patterson
authors.forename: Robert
authors.initials: R
authors.lastname: Garman
authors.forename: Stephen
authors.initials: S
authors.lastname: Sagar
authors.forename: Dwain
authors.initials: D
authors.lastname: Tolbert
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004487:Edema / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D018682:GABA Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests; D020888:Vigabatrin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D018682:GABA Agents; D020888:Vigabatrin