A novel phospholipid derivative of indomethacin, 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], shows superior safety and similar efficacy in reducing brain amyloid beta 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-{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.
Dvir
E
E
D-Pharm Ltd., Rehovot 76123, Israel. edvir@dpharm.com
Friedman
J E
JE
Lee
J Y
JY
Koh
J Y
JY
Younis
F
F
Raz
S
S
Shapiro
I
I
Hoffman
A
A
Dahan
A
A
Rosenberg
G
G
Angel
I
I
Kozak
A
A
Duvdevani
R
R
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D015232:Dinoprostone / Q000096:biosynthesis; D004338:Drug Combinations; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000032:analysis*; D010713:Phosphatidylcholines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; C514017:DP 155; D004338:Drug Combinations; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D015232:Dinoprostone; D007213:Indomethacin