Govendir M, Canfield P J, Emslie D R, Watson A D J, Church D B
Faculty of Veterinary Science, The University of Sydney, New South Wales.
Aust Vet J. 2002 Jan-Feb;80(1-2):75-82; discussion 82.
To determine whether induction of pancreatic necrosis and islet proliferation by d,l-ethionine has potential for treating dogs with beta-cell insufficiency.
Eighteen mixed breed dogs of both sexes were given d,l-ethionine at 100 mg/kg three times weekly for 2 weeks; 6 dogs were euthanased at 2, 14 and 28 d after the last dose.
Clinical signs during administration and recovery were assessed. Routine biochemical analyses were performed before each ethionine dose and then once weekly. Faecal samples were examined weekly for malassimilated nutrients and blood. Blood coagulation screening tests (OSPT and APTT) were determined on four dogs after ethionine administration. Intravenous glucose tolerance tests were conducted before the first and after the last ethionine dose and then fortnightly. All dogs were necropsied and pancreas, liver, kidney and jejunum were examined microscopically.
During ethionine administration all animals displayed vomiting, inappetence, diarrhoea (often with blood), weight loss and depression. Three dogs were euthanased prematurely due to severe illness, but those allowed to recover were eating and brighter 7 d after cessation of ethionine administration. Serum concentrations of TLI, amylase and lipase increased initially, then decreased, during administration but retumed to normal during recovery. Concentrations of ALT, ALP, unconjugated and conjugated bilirubin increased during administration then decreased slowly. Histological examination revealed hepatic lipidosis and necrosis, but no renal or jejunal lesions. In most dogs, faecal examination demonstrated increased undigested starch and muscle, as well as increased digested and undigested fat, during ethionine administration or early during the recovery period, suggesting transient malassimilation. APTT was unchanged but OSPT was prolonged in all dogs. There was no impairment of insulin secretion or glucose intolerance and C-peptide concentrations were unaffected. Immediately after ethionine administration there was delayed insulin degradation and by day 43 there was evidence of increased insulin sensitivity.
d,l-ethionine administration in dogs appeared not to interfere with insulin secretion, but caused clinical signs and laboratory changes indicative of pancreatic exocrine necrosis, severe hepatobiliary disease and transient malassimilation. Pancreatic and hepatic dysfunction was severe but clinical recovery occurred after ethionine administration ceased. The severe side-effects observed with d,l-ethionine should preclude its potential use for treating diabetes mellitus in dogs.
确定d，l-乙硫氨酸诱导胰腺坏死和胰岛增殖是否有治疗β细胞功能不全犬的潜力。
18只不同性别的杂种犬，每周3次给予100mg/kg的d，l-乙硫氨酸，持续2周；在最后一剂后的第2、14和28天对6只犬实施安乐死。
评估给药和恢复期间的临床症状。在每次乙硫氨酸给药前及之后每周进行一次常规生化分析。每周检查粪便样本中的营养物质吸收不良和血液情况。对4只犬在乙硫氨酸给药后进行凝血筛查试验（OSPT和APTT）。在首次乙硫氨酸给药前、最后一次给药后及之后每两周进行一次静脉葡萄糖耐量试验。对所有犬进行尸检，并对胰腺、肝脏、肾脏和空肠进行显微镜检查。
在乙硫氨酸给药期间，所有动物均出现呕吐、食欲不振、腹泻（常带血）、体重减轻和抑郁。3只犬因重病提前实施安乐死，但那些恢复的犬在乙硫氨酸给药停止后7天开始进食且状态好转。给药期间血清TLI、淀粉酶和脂肪酶浓度最初升高，然后下降，但恢复期间恢复正常。ALT、ALP、未结合胆红素和结合胆红素浓度在给药期间升高，然后缓慢下降。组织学检查显示肝脂肪变性和坏死，但无肾脏或空肠病变。在大多数犬中，粪便检查显示在乙硫氨酸给药期间或恢复早期，未消化的淀粉和肌肉增加，以及消化和未消化的脂肪增加，提示短暂的吸收不良。所有犬的APTT未改变，但OSPT延长。胰岛素分泌或葡萄糖耐量无损害，C肽浓度未受影响。乙硫氨酸给药后立即出现胰岛素降解延迟，到第43天有胰岛素敏感性增加的证据。
犬给予d，l-乙硫氨酸似乎不干扰胰岛素分泌，但引起临床症状和实验室变化，提示胰腺外分泌坏死、严重肝胆疾病和短暂的吸收不良。胰腺和肝功能障碍严重，但在乙硫氨酸给药停止后出现临床恢复。观察到的d，l-乙硫氨酸的严重副作用应排除其在犬糖尿病治疗中的潜在用途。
