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

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2006
Contact PI Name:
Eran Dvir
Contact PI Affiliation:
D-Pharm Ltd., Rehovot, Israel
Co-Authors:
J.E. Friedman, J.Y. Lee, J.Y. Koh, F. Younis, S. Raz, I. Shapiro, A. Hoffman, A. Dahan, G. Rosenberg, I. Angel, A. Kozak, R. Duvdevani
Primary Reference (PubMED ID):
16763096
Funding Source:
Israeli Consortium of Pharmalogica
D-Pharm Ltd.
Study Goal and Principal Findings:

The goal of the study is to test DP-155, a phospholipid derivative of NSAID indomethacin, safety and effects on brain Aβ levels in Tg2576 mice. Past studies have shown indomethacin inhibits Aβ formation via gamma-secretase inhibition through a COX-independent process in addition to its COX dependent anti-inflammatory and neuroprotective effects. However, long-term indomethacin use is limited by significant gastrointestinal and renal toxicities. In this study, DP-155, which is a lipid-modified indomethacin comprised of indomethacin linked to lecithin, had reduced toxicity as compared to indomethacin, and was equally efficacious in reducing brain Aβ. DP-155 had 3.5 times higher brain to serum ratio, which explains why DP-155 is efficacious in reducing brain Aβ with significantly lower toxicity in the gut and kidney, making this compound a potential therapeutic for Alzheimer's disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Indomethacin
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Cyclooxygenase 1 (COX 1)
Open Targets
Pharos
Agora
Therapeutic Target:
Cyclooxygenase 2 (COX 2)
Open Targets
Pharos
Agora
Therapy Type:
Small Molecule
Therapeutic Agent:
DP-155
PubMed
PubChem
Patents
Therapeutic Target:
Cyclooxygenase 1 (COX 1)
Open Targets
Pharos
Agora

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
Tg2576
ALZFORUM
Strain/Genetic Background:
Not Reported
Species:
Rat
Model Type:
Outbred
Model Name:
Sprague Dawley
Strain/Genetic Background:
Not Applicable

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Biochemical
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Pharmacokinetics
Drug Concentration-Serum
Drug Concentration-Brain
Oral Bioavailability (F%)
Plasma t1/2
Tmax
Cmax
Area Under the Curve (AUC)
Brain/Plasma Ratio
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Toxicology
General Activity
Toxicity-Gastrointestinal (GI)
Toxicity-Renal
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Source URL: http://alzped.nia.nih.gov/novel-phospholipid-derivative