Sato M, Rippy M K, Bryant H U
Department of Endocrine Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
FASEB J. 1996 Jun;10(8):905-12. doi: 10.1096/fasebj.10.8.8666168.
For the first time, four well-characterized compounds from four distinct chemical classes were directly compared for efficacy and potency in hone, uteri, lipids, and adipose tissues in an ovariectomized model with 6 month old rats. Five weeks of oral dosing confirmed that ethynyl estradiol, tamoxifen, and raloxifene are potent inhibitors of the loss in volumetric bone mineral density (BMD, mg/cc) induced by ovariectomy, as measured by computed tomography. In the metaphysis of distal femora from ovariectomized rats, analysis showed a significant 12-20% decrease (P< 0.01) in the BMD. Linear regression analysis was used to calculate half-maximal efficacious doses for ethynyl estradiol ED(50) =0.04mg /kg, which was threefold more potent than tamoxifen, which in turn was threefold more potent than raloxifene, which was more efficacious than nafoxidine. In the uterus, raloxifene had minimal effects on the endometrium and smaller effects on uterine eosinophil peroxidase activity than nafoxidine, tamoxifen, or estrogen, respectively. Estrogen was the most potent in reducing cholesterol levels in ovariectomized rats, whereas tamoxifen and nafoxidine were more effective than raloxifene in blocking gain in body weight. Distinct compounds had advantages in the management of bone, uterine, serum cholesterol, and adipose tissues after ovariectomy. The distinct pattern of pharmacological effects may be best understood in terms of their respective chemical structure, specifically estrogens, benzothiophenes (raloxifene), dihydronapthylenes (nafoxidine), and triphenylethylenes (tamoxifen). These data point to advantages of separate compounds in the management of bone, uterine, serum cholesterol, and adipose tissues after estrogen deficiency, and show that the benzothiophene raloxifene has potentially important advantages over estrogen, tamoxifen, or nafoxidine in the uterus.
首次在6月龄去卵巢大鼠模型中，对来自四个不同化学类别的四种特征明确的化合物在骨骼、子宫、脂质和脂肪组织中的功效和效力进行了直接比较。为期五周的口服给药证实，乙炔雌二醇、他莫昔芬和雷洛昔芬是去卵巢诱导的体积骨矿物质密度（BMD，mg/cc）损失的有效抑制剂，通过计算机断层扫描测量。在去卵巢大鼠股骨远端干骺端，分析显示骨矿物质密度显著降低12 - 20%（P < 0.01）。线性回归分析用于计算乙炔雌二醇的半数最大有效剂量ED(50) = 0.04mg/kg，其效力是他莫昔芬的三倍，而他莫昔芬的效力又是雷洛昔芬（比奈法唑酮更有效）的三倍。在子宫中，雷洛昔芬对子宫内膜的影响最小，对子宫嗜酸性粒细胞过氧化物酶活性的影响分别比对奈法唑酮、他莫昔芬或雌激素的影响小。雌激素在降低去卵巢大鼠胆固醇水平方面最有效，而他莫昔芬和奈法唑酮在阻止体重增加方面比雷洛昔芬更有效。不同的化合物在去卵巢后的骨骼、子宫、血清胆固醇和脂肪组织管理方面具有优势。从各自的化学结构，特别是雌激素、苯并噻吩（雷洛昔芬）、二氢萘（奈法唑酮）和三苯乙烯（他莫昔芬）方面，可能最好理解不同的药理作用模式。这些数据表明不同化合物在雌激素缺乏后骨骼、子宫、血清胆固醇和脂肪组织管理方面的优势，并表明苯并噻吩雷洛昔芬在子宫方面相对于雌激素、他莫昔芬或奈法唑酮具有潜在的重要优势。
