title: 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.
authors.affiliation: Division of Rheumatology, UCLA School of Medicine, Los Angeles, CA 90095-1670, USA. ebrahn@mednet.ucla.edu
authors.forename: Ernest
authors.initials: E
authors.lastname: Brahn
authors.forename: Nathan
authors.initials: N
authors.lastname: Schoettler
authors.forename: Sarah
authors.initials: S
authors.lastname: Lee
authors.forename: Mona L
authors.initials: ML
authors.lastname: Banquerigo
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001682:Biological Availability; D024043:Collagen Type II; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005434:Flow Cytometry; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D024043:Collagen Type II; D004852:Epoxy Compounds; C488724:PPI 2458; D014633:Valine