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Morphologic Changes of Terbinafine Intoxication
實驗結果顯示，急性中毒試驗於灌食劑量達每公斤體重3克以上時，可見實驗鼠發生震顫、角弓反張、運動失調和四肢做划水動作等神經症狀，且發生臨床症狀的起始時間與劑量成反比，雌鼠之發生率高於雄鼠。在血液學檢查方面，檢測值與對照組比較，無顯著差異性。在血清生化學檢查方面，肝功能檢測以天門冬酸轉氨酉每 (aspartate transaminase)及氨基丙酸轉氨酉每 (alanine transaminase)數值上升具顯著差異性。腎功能檢測以血清肌酸酐(serum creatinine)具顯著差異性。在肉眼病變方面，除觀察到胃和小腸的血管怒張充血外，其他臟器均無明顯的病變。組織切片中，可見到延腦的神經元有中央色質溶解、核濃縮、細胞皺縮、溶解和噬神經現象。所有灌食藥液之實驗鼠，均見到肝臟組織有輕微空泡化情形，但於腎臟並無明顯病變。在半薄切片中，可見到大小不一之深藍色顆粒於肝、腎細胞質。以穿透式電子顯微鏡觀察有病變之神經元，發現細胞極度濃縮，核仁明顯脹大，細胞內的胞器消失。於肝、腎細胞質內，觀察到圓形、大小不一之脂肪顆粒，內含不規則的結晶物。灌食terbinafine稀釋液每公斤體重1克的實驗鼠，可發現類似膽汁樣不規則物及微膽管擴張的病變。在灌食劑量每公斤體重3克之實驗鼠發生病變時間的測定上，可見神經元變性於灌食後2小時就發生。肝臟組織出現脂肪滴，發生在灌食後6小時，細胞壞死則發生於灌食後10小時。腎臟組織在灌食後10小時出現脂肪滴。
The purpose of the study is to define the toxic effects of terbinafine, and to explore the relationship among the pathologies and the hematological and the biochemical abnormalities in animals. The laboratory animals were administered terbinafine with different dosages at various time intervals. We closely observed the clinical signs, the hemogram, the serum biochemistry, as well as the histopathology. We also performed the electron microscopy for further examination of the brain, the liver and the kidney. In acute intoxication study, the guinea pigs developed the neurological signs including rigidity, tremor, spasm, opisthotonus, ataxia and paddling when the dosage of terbinafine more than 3 g/kg,bw. The onset of the neurological signs appeared earlier when the dosage increased. The morbidity of the female guinea pigs was higher than that of the male. The serum levels of aspartate transaminase, alanine transaminase and creatinine were all increased significantly, indicating the hepatic and the renal function impairment. However, the hemogram revealed no significant difference between the experimental and the control groups. Grossly, only the vascular engorgement on stomach and intestine could be found, otherwise, no visible abnormalities were found in other organs. The pathology of the medullar oblongata revealed central chromatolysis, nuclear pyknosis, neuronophagia, and cytolysis in animals administered terbinafine over 3 g/kg,bw. Only mild fatty change was found in the liver, but no pathologic change was observed in the kidney of all terbinafine-treated guinea pigs. In semithin section, many dark blue granules were present in the hepatocytes and the renal tubule cells. The ultrastructural examination revealed pyknosis, shrinkage and loss of organelles in the degenerated neurons. Fat droplets containing electron-dense crystallized substances in the hepatocytes and the renal tubule cells. The bile substances were also found in hepatocytes. In addition, the bile canaliculi dilated remarkably in animals administered with terbinafine 1 g/kg,bw. The onset of the neuron degeneration was first appeared at second hour after drug administration. The onset of the occurrence of fat droplets and necrosis in hepatocytes was observed at sixth hour and at tenth hour separately. Fat droplets in the renal tubule cells appeared at tenth hour after drug administration. In subacute intoxication study, there were not any neurological signs in rats treated with terbinafine 250mg /40kg,bw daily for six weeks. In the meanwhile, the hemogram, the serum biochemistry, and the histopathology revealed no significant difference between the experimental and the control group. Ultrastructurally, the presence of the fat droplets in the hepatocytes and the renal tubule cells was similar to that found in mice treated with large toxic dose. In summary, terbinafine in high dosage is toxic to the neurons, the hepatocytes, and the renal tubule cells, and it is potentially toxic to the liver at therapeutic dosage for longer than six weeks. Thus, we strongly suggest that liver function tests should be performed in any patients taking terbinafine for longer than six weeks.
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