Sato M, Turner C H, Wang T, Adrian M D, Rowley E, Bryant H U
Department of Endocrine Research, Lilly Corporate Center, Indianapolis, Indiana, USA.
J Pharmacol Exp Ther. 1998 Oct;287(1):1-7.
Body weight, uteri, serum cholesterol and bones were shown previously in vivo to be sensitive to circulating levels of estrogen, as well as to synthetic, nonsteroidal ligands termed selective estrogen receptor modulators (SERM). In this study, we examined the in vivo effects of a new potent SERM on these tissues in 6-month-old, ovariectomized rats that were orally dosed with 0.0001-10 mg/kg/day LY353381.HCl for 5 weeks. LY353381.HCl prevented the ovariectomy-induced increase in body weight and serum cholesterol levels of treated rats and lowered them to below sham levels in a dose dependent manner, with maximum efficacy similar to estrogen or raloxifene. However, LY353381.HCl was consistently more potent than raloxifene, with a half maximal efficacious dose of 0.001 mg/kg for the reduction of body weight and cholesterol. In the uterus, LY353381.HCl had marginal effects on uterine weight compared to ovariectomized controls (OVX) like raloxifene, but unlike estrogen. Histological examination of uterine epithelial cell height showed little to no stimulatory effect of LY353381.HCl on the endometrium. Quantitative computed tomographic analyses (pQCT) of tibiae showed that LY353381.HCl prevented loss of bone due to ovariectomy with an ED50 of about 0.01 mg/kg with maximal efficacy observed at 0.1-1 mg/kg/day. Maximally attainable bone mineral density and content with LY353381.HCl were not significantly different from Sham or ovariectomized rats treated with estrogen or raloxifene. Interestingly, assessment of bone quality by biomechanical analyses showed that LY353381.HCl preserved the strength of the femora neck and midshaft, while improving the Young's modulus of cortical bone to beyond estrogen, raloxifene or sham levels. In uteri of immature rats treated with estrogen, LY353381.HCl antagonized the estrogen-induced elevation in uterine weight down to vehicle-dosed control levels with ED50 of 0.03 mg/kg/day. Therefore, LY353381.HCl was 30-100 times more potent than raloxifene in preventing ovariectomy effects on body weight, serum cholesterol and bone, while maintaining estrogen antagonist effects on the uterus. These animal data suggest that LY353381.HCl may have advantages over estrogen or raloxifene in the prevention of bone loss and treatment of other tissues in postmenopausal women.
先前在体内研究中发现，体重、子宫、血清胆固醇和骨骼对循环中的雌激素水平以及称为选择性雌激素受体调节剂（SERM）的合成非甾体配体敏感。在本研究中，我们检查了一种新型强效SERM对6个月大的去卵巢大鼠这些组织的体内作用，这些大鼠口服0.0001 - 10 mg/kg/天的盐酸LY353381，持续5周。盐酸LY353381可预防去卵巢诱导的受试大鼠体重和血清胆固醇水平升高，并以剂量依赖性方式将其降至假手术组水平以下，最大功效与雌激素或雷洛昔芬相似。然而，盐酸LY353381始终比雷洛昔芬更有效，降低体重和胆固醇的半数最大有效剂量为0.001 mg/kg。在子宫方面，与雷洛昔芬一样，盐酸LY353381与去卵巢对照组（OVX）相比，对子宫重量的影响很小，但与雌激素不同。子宫上皮细胞高度的组织学检查显示，盐酸LY353381对子宫内膜几乎没有刺激作用。胫骨的定量计算机断层扫描分析（pQCT）表明，盐酸LY353381可预防去卵巢导致的骨质流失，半数有效剂量约为0.01 mg/kg，在0.1 - 1 mg/kg/天观察到最大功效。盐酸LY353381所能达到的最大骨矿物质密度和含量与假手术组或用雌激素或雷洛昔芬治疗的去卵巢大鼠无显著差异。有趣的是，通过生物力学分析评估骨质量表明，盐酸LY353381可保持股骨颈和骨干的强度，同时将皮质骨的杨氏模量提高到超过雌激素、雷洛昔芬或假手术组的水平。在用雌激素治疗的未成熟大鼠子宫中，盐酸LY353381可将雌激素诱导的子宫重量升高拮抗至溶剂给药对照组水平，半数有效剂量为0.03 mg/kg/天。因此，在预防去卵巢对体重、血清胆固醇和骨骼的影响方面，盐酸LY353381比雷洛昔芬有效30 - 100倍，同时对子宫保持雌激素拮抗作用。这些动物数据表明，在预防绝经后妇女骨质流失和治疗其他组织方面，盐酸LY353381可能比雌激素或雷洛昔芬更具优势。
