Badger A M, Blake S, Kapadia R, Sarkar S, Levin J, Swift B A, Hoffman S J, Stroup G B, Miller W H, Gowen M, Lark M W
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Arthritis Rheum. 2001 Jan;44(1):128-37. doi: 10.1002/1529-0131(200101)44:1<128::AID-ANR17>3.0.CO;2-M.
To evaluate the effects of SB 273005, a potent, orally active nonpeptide antagonist of the integrin avbeta3 vitronectin receptor, on joint integrity in rats with adjuvant-induced arthritis (AIA).
Male Lewis rats with AIA were orally dosed either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 273005. Efficacy was determined by measurement of paw inflammation, assessment of bone mineral density using dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), and histologic evaluation.
SB 273005 is a potent antagonist of the closely related integrins, avbeta3 (Ki = 1.2 nM) and alphavbeta5 (Ki = 0.3 nM). When SB 273005 was administered prophylactically to AIA rats twice per day, it inhibited paw edema at doses of 10, 30, and 60 mg/kg, by 40%, 50%, and 52%, respectively. Therapeutic administration twice daily was also effective, and a reduction in paw edema was observed at 30 mg/kg and 60 mg/kg of the antagonist (by 36% and 48%, respectively). SB 273005 was also effective when administered once per day, both prophylactically and therapeutically. Significant improvement in joint integrity in treated rats was shown using DEXA and MRI analyses. These findings were confirmed histologically, and significant protection of bone, cartilage, and soft tissue was observed within the joint.
Symptoms of AIA in rats were significantly reduced by either prophylactic or therapeutic treatment with the alphavbeta3 antagonist, SB 273005. Measurements of paw inflammation and of bone, cartilage, and soft tissue structure indicated that this compound exerts a protective effect on joint integrity and thus appears to have disease-modifying properties.
评估SB 273005（一种有效的、口服活性的整合素αvβ3玻连蛋白受体非肽拮抗剂）对佐剂诱导性关节炎（AIA）大鼠关节完整性的影响。
对患有AIA的雄性Lewis大鼠进行预防性给药（第0 - 20天）或治疗性给药（第10 - 20天），给予SB 273005。通过测量爪部炎症、使用双能X线吸收法（DEXA）评估骨矿物质密度、磁共振成像（MRI）以及组织学评估来确定疗效。
SB 273005是密切相关的整合素αvβ3（Ki = 1.2 nM）和αvβ5（Ki = 0.3 nM）的有效拮抗剂。当每天两次对AIA大鼠进行预防性给予SB 273005时，在10、30和60 mg/kg剂量下，分别使爪部水肿抑制了40%、50%和52%。每天两次进行治疗性给药也有效，在30 mg/kg和60 mg/kg拮抗剂剂量下观察到爪部水肿减轻（分别减轻36%和48%）。SB 273005每天给药一次时，无论是预防性还是治疗性给药均有效。使用DEXA和MRI分析显示，治疗大鼠的关节完整性有显著改善。这些发现通过组织学得到证实，并且在关节内观察到对骨、软骨和软组织有显著保护作用。
用αvβ3拮抗剂SB 273005进行预防性或治疗性治疗可显著减轻大鼠AIA的症状。爪部炎症以及骨、软骨和软组织结构的测量表明，该化合物对关节完整性具有保护作用，因此似乎具有改善病情的特性。
