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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 8, 2006; DOI: 10.1124/jpet.106.103184

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Received for publication February 22, 2006.
Revised May 31, 2006.
Accepted for publication June 7, 2006.

A novel phospholipid derivative of indomethacin, DP-155, shows superior safety and similar efficacy in reducing brain amyloid {beta} in an Alzheimer's disease model

Eran Dvir 1*, Jonathan E. Friedman 1, Joo-Yong Lee 2, Jae-Young Koh 2, Firas Younis 1, Shaul Raz 1, Israel Shapiro 1, Amnon Hoffman 3, Arik Dahan 3, Gilad Rosenberg 1, Itzchak Angel 1, Alex Kozak 1, Revital Duvdevani 1

1 D-Pharm Ltd. 2 University of Ulsan 3 The Hebrew University of Jerusalem

* Address correspondence to: E-mail: edvir{at}dpharm.com

Abstract

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 developed DP-155, a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007-0.28 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-PGE2. An equimolar oral dose of DP-155 or indomethacin, administered every 4h 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 22h and 93h, respectively, compared to 10h and 24h 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 to indomethacin, DP-155 has significantly lower toxicity in the gut and kidney whilst 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.


Key words: Alzheimer's disease, Amyloid beta, gastrointestinal safety, indomethacin, nephrotoxicity, phospholipid


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