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Involution of collagen-induced arthritis with an angiogenesis inhibitor, PPI-2458.

Abstract
Pannus formation, in both rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), is angiogenesis-dependent. PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R,3S,5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)oxiranyl]-1-oxaspiro(2*5)oct-6-yl ester], a new fumagillin derivative known to inhibit methionine aminopeptidase 2 (MetAP-2) and endothelial proliferation at the late G(1) phase, was evaluated in CIA rats to study its potential to involute synovitis. Arthritic syngeneic LOU rats received either a vehicle control or various dosages of oral, intravenous, or subcutaneous PPI-2458. Plasma samples were analyzed to determine a pharmacokinetic profile of PPI-2458, and whole blood was evaluated by flow cytometry to assess the effect on lymphocyte subsets. At 15 mg/kg i.v., 30 mg/kg s.c., or 100 mg/kg p.o., there was a significant reduction in clinical severity scores (p < 0.001) and blinded radiographic scores (p < 0.001) compared with vehicle control groups. Structural damage was virtually eliminated with PPI-2458. Continuous inhibition of MetAP-2 was needed to maintain benefits, although pannus involution could be achieved with the inhibitor when escape flares occurred. Pharmacokinetic analysis after a single p.o. dose showed a rapid T(max) value of 15 min followed by biphasic elimination (t(1/2), approximately 20 min and t(1/2), approximately 5 h) and an estimated oral bioavailability of approximately 15%. Flow cytometry revealed a dose-dependent decrease in white blood cells and lymphocytes manifested as decreases in circulating CD3+ T cells and natural killer cells. PPI-2458, however, did not seem to be immunosuppressive, as determined by delayed-type hypersensitivity or IgG antibody assays. These studies indicate that the MetAP-2 inhibitor PPI-2458 can regress established CIA and that angiogenic mechanisms might be important targets in the treatment of other pannus-mediated diseases such as RA.
AuthorsErnest Brahn, Nathan Schoettler, Sarah Lee, Mona L Banquerigo
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 329 Issue 2 Pg. 615-24 (May 2009) ISSN: 1521-0103 [Electronic] United States
PMID19218530 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Angiogenesis Inhibitors
  • Collagen Type II
  • Epoxy Compounds
  • PPI 2458
  • Valine
Topics
  • Administration, Oral
  • Angiogenesis Inhibitors (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Animals
  • Arthritis, Experimental (chemically induced, drug therapy, immunology, pathology)
  • Biological Availability
  • Collagen Type II
  • Epoxy Compounds (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Flow Cytometry
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Molecular Structure
  • Neovascularization, Pathologic (immunology, pathology, prevention & control)
  • Rats
  • Rats, Inbred Strains
  • Valine (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)

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