A novel phospholipid derivative of indomethacin, DP-155 [mixture of 1-steroyl and 1-palmitoyl-2-{4-[ 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]butanoyl}-sn-glycero-3-phosophatidyl choline], shows superior safety and similar efficacy in reducing brain amyloid β in an Alzheimer's disease model

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{ 4-[1-( p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] butanoyl}-Sn-glycero-3-phosophatidyl 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 bicycloprostaglandin 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 A beta 42 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 A beta 42 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 A beta 42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155' s potential as an improved indomethacin-based therapy for AD.