Dvir E, Friedman J E, Lee J Y, Koh J Y, Younis F, Raz S, Shapiro I, Hoffman A, Dahan A, Rosenberg G, Angel I, Kozak A, Duvdevani R
D-Pharm Ltd., Rehovot 76123, Israel.
J Pharmacol Exp Ther. 2006 Sep;318(3):1248-56. doi: 10.1124/jpet.106.103184. Epub 2006 Jun 8.
Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.
吲哚美辛已被建议用于治疗阿尔茨海默病（AD），但其应用因胃肠道和肾脏毒性而受到限制。为克服这一局限性，以色列雷霍沃特的D-Pharm有限公司研发了DP-155（1-硬脂酰基和1-棕榈酰基-2-{6-[1-(对氯苯甲酰基)-5-甲氧基-2-甲基-3-吲哚基乙酰胺基]己酰基}-Sn-甘油-3-磷酸胆碱[已修正]的混合物），一种吲哚美辛的卵磷脂衍生物。通过以0.007至0.28 mmol/kg的剂量范围每日口服DP-155或吲哚美辛对大鼠进行安全性测试。DP-155导致的胃肠道溃疡发生率显著低于吲哚美辛（低10倍），且溃疡出现延迟。DP-155导致的肾脏毒性迹象，即尿量减少和尿N-乙酰氨基糖苷酶与肌酐比值升高，比吲哚美辛低5倍。吲哚美辛可降低尿双环前列腺素E2，但等摩尔剂量的DP-155则无此作用。每4小时口服一次等摩尔剂量的DP-155或吲哚美辛，连续给药3天，在降低Tg2576小鼠脑内β淀粉样蛋白42（Aβ42）水平方面效果相当。吲哚美辛是DP-155在血清中的主要代谢产物。口服DP-155后，吲哚美辛在血清和脑内的半衰期分别为22小时和93小时，而口服吲哚美辛后分别为10小时和24小时。DP-155的脑血比是吲哚美辛的3.5倍。这一发现解释了尽管DP-155产生的吲哚美辛全身血药浓度较低，但DP-155仍能有效降低脑内Aβ42水平。总之，与吲哚美辛相比，DP-155在胃肠道和肾脏中的毒性显著更低，同时在降低Tg2576小鼠脑内Aβ42水平方面保持与吲哚美辛相似的疗效。这种更优越的安全性表明DP-155作为一种改良的基于吲哚美辛的AD治疗药物具有潜力。
