title: Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis.
abstract: Here, we describe the improved antiarthritic properties of a nitric oxide-releasing derivative of prednisolone that includes a sparing of the effects on bone. Glucocorticoids are widely used in the treatment of chronic inflammatory pathologies, but their use is often accompanied by side effects, including osteoporosis. Recently, a new steroid able to release low levels of nitric oxide showed potent inhibition of leukocyte trafficking and chemokine generation in models of acute inflammation. The objective of this study was to assess the anti-inflammatory activity of this nitric-oxide releasing glucocorticoid, nitro-prednisolone (NCX-1015), in parallel with the parent compound prednisolone and a control molecule lacking an NO group, (NCX-1016), in a model of rat collagen-induced arthritis. Dosing of rats with NCX-1015 (0.4-4 micromol/kg, i.p.) greatly reduced all parameters of inflammation. A significant but inferior anti-inflammatory effect also was obtained with prednisolone. Collagen-induced arthritic rats had elevated pyridinoline values (> 60% over naïve rats), indicating bone and cartilage erosion; this increase was prevented by NCX-1015 but not by prednisolone or NCX-1016 treatment. In vitro, prednisolone (1 nM), but not NCX-1015, elevated bone resorbing activity of rat primary osteoclasts. In conclusion, NCX-1015 is a steroid derivative with a potential for the treatment of chronic inflammatory pathologies and that has milder side effects anticipated on the bone compartment.
authors.affiliation: William Harvey Research Foundation, Pharmacology Division of St. Bartholomew's and Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: Lucia
authors.initials: L
authors.lastname: Mancini
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001168:Arthritis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001219:Aspartate Aminotransferases / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D001862:Bone Resorption / Q000503:physiopathology; D003094:Collagen / Q000494:pharmacology; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004573:Electrolytes / Q000097:blood; D005260:Female; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D011239:Prednisolone / Q000031:analogs & derivatives / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D014508:Urea / Q000097:blood
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D016207:Cytokines; D004573:Electrolytes; D020030:Nitric Oxide Donors; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); D014508:Urea; D003094:Collagen; D011239:Prednisolone; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase