DESCRIPTION (provided by applicant): The lanthanides, also known as the rare earths, comprise a series of 15 elements spanning atomic numbers 57-71. Lanthanide ions (Ln3+) are of approximately the same ionic radius as Ca2+ ions, and share many other chemical properties, including ligand preference and geometry. They frequently replace Ca2+ in an isomorphous fashion on biological macromolecules, organelles and cells. Because of their greater charge: volume ratio, binding constants are higher for than Ca2+, and they often interfere with Ca-dependent biological functions. One example of importance to this proposal, is the ability of to suppress macrophage activation in vivo. have been shown to reduce mortality in rats challenged by anaphylaxis, endotoxin, pancreatitis and other macrophage-dependent pathologies. Funding is requested to determine whether also inhibit the development of experimental models of RA in rats. Two such models will be evaluated: antigen-induced arthritis, using ovalbumin as the inciting antigen, and adjuvant arthritis. These two models are selected because has been shown to inhibit anaphylactic responses to ovalbumin in sensitized animals, and also to suppress inflammatory responses to Freund's complete adjuvant, the inciting agent in adjuvant arthritis in rats. Three different members of the lanthanide series will be tested: lanthanum (Ln3+), the largest member of the series, gadolinium (Gd3+), which lies in the middle of the series and has been widely used as a therapeutic agent in rats, and lutetium (Ln3+), the smallest lanthanide. will be evaluated both as free cations and as complexes with citrate to improve their solubility and mobility. Lanthanides will be injected systemically and intra-articularly. A successful outcome to these studies will have identified the basis for a potential new, very inexpensive anti-rheumatic agent whose mode of action differs from that of existing drugs.
|Effective start/end date||9/25/03 → 8/31/05|