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.