Chronic toxicity of the anticonvulsant zonisamide in beagle dogs. Export

@article{citeulike:5024884, abstract = {The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum.}, author = {Walker, R. M. and DiFonzo, C. J. and Barsoum, N. J. and Smith, G. S. and Macallum, G. E.}, citeulike-article-id = {5024884}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/3220211}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=3220211}, issn = {0272-0590}, journal = {Fundamental and applied toxicology : official journal of the Society of Toxicology}, keywords = {anticonvulsants, pharmacology, seizures, toxicity}, month = {August}, number = {2}, pages = {333--342}, posted-at = {2009-06-30 19:25:38}, priority = {2}, title = {Chronic toxicity of the anticonvulsant zonisamide in beagle dogs.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/3220211}, volume = {11}, year = {1988} }

TY - JOUR ID - citeulike:5024884 L3 - citeulike-article-id:5024884 N2 - The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum. IS - 2 JF - Fundamental and applied toxicology : official journal of the Society of Toxicology SN - 0272-0590 EP - 342 TI - Chronic toxicity of the anticonvulsant zonisamide in beagle dogs. VL - 11 SP - 333 KW - anticonvulsants KW - pharmacology KW - seizures KW - toxicity AU - Walker, RM AU - DiFonzo, CJ AU - Barsoum, NJ AU - Smith, GS AU - Macallum, GE PY - 1988/08// UR - http://view.ncbi.nlm.nih.gov/pubmed/3220211 ER -