Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes - A potential treatment for aseptic loosening of total joint components

Background: Pentoxifylline (Trental) is a methylxanthine-derivative drug th at has been used for more than twenty years in the treatment of peripheral vascular disease. Pentoxifylline is also a potent inhibitor of tumor necros is factor-alpha (TNF-alpha) secretion, both in vitro and in vivo, and has d emonstrated efficacy in the treatment of certain animal and human inflammat ory diseases. Pentoxifylline has a potential therapeutic role in the treatm ent of aseptic loosening of total joint replacement components because it i nhibits TNF-alpha secretion by particle-stimulated human peripheral blood m onocytes. The purpose of our study was to determine whether the particle-st imulated secretion of TNF-alpha by peripheral blood monocytes was inhibited in volunteers who had received pentoxifylline orally. Methods: Human peripheral blood monocytes were harvested from eight healthy volunteers and were exposed to three different concentrations of titanium particles or to 500 ng/mL of lipopolysaccharide as a positive control. The same volunteers were then given pentoxifylline (400 mg, five times per day) for seven days. Their peripheral blood monocytes were again isolated and e xposed to experimental conditions, and the TNF-alpha levels were measured. Results: The peripheral blood monocytes from all eight volunteers showed a significant reduction in TNF-alpha release following oral treatment with pe ntoxifylline. This reduction was observed at exposures of 10(7) and 10(6) t itanium particles/mL and in the lipopolysaccharide treated group, but not a t 10(5) particles/mL. Conclusions: To our knowledge, this is the first study to demonstrate the a bility of an oral drug to decrease the release of TNF-alpha from human peri pheral blood monocytes exposed ex vivo to particle debris. TNF-alpha is inv olved in the pathogenesis of osteolysis and subsequent loosening of total j oint arthroplasty components. The ability to suppress the release of TNF-al pha in patients with a total joint replacement may help to control osteolys is and to reduce the development of aseptic loosening. This effect could in crease implant longevity and decrease the need for revision arthroplasty.