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Career situation of first and presenting author Post-doctoral fellow. Introduction The use of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) is limited by serious adverse effects. Some effects, such as stomatitis and gastric ulcer, can be alleviated by folate supplement. Others are folate-independent, e.g. fibrosis of liver and lung. Moreover, MTX further elevates the micronuclei count, which is generally already increased in RA. In RA, inflamed tissue is characterized by up to 100-fold increased concentrations of reactive oxygen species (ROS, including hydrogen peroxide) compared to healthy tissue. A novel MTX prodrug, ROS101 in development for the treatment of RA, releases MTX at exposure to ROS. This restricts MTX exposure to target tissues with increased ROS levels, e.g. the synovial membrane in RA. Objectives To investigate the effect and toxicity of a targeted MTX prodrug in a rat CIA model of rheumatoid arthritis. Methods ROS101 was tested in a collagen induced arthritis (CIA) model in dark agouti (DA) rats (10 per group) against vehicle and 0.3 mg MTX i.p./day at equimolar doses. Arthritis was induced by s.c. injection of an emulsion of collagen type II in complete Freund’s adjuvant. Treatment was initiated at a mean arthritis severity score of 2/60. Blinded disease evaluation took place 3 times/week from day 10. Bone marrow cells for micronucleus test were obtained from the femur, pictures captured with LARS.4.8 software and analyzed blinded. Individual rat data were included until termination. Results Mean and maximum arthritis severity score was reduced in rats in the ROS101 group compared to vehicle (mean score 6.3±3.1 vs. 14.1±3.3, mean±SEM); (max score 12.6±5.3 vs. 32.3±5.3, mean±SEM, p Conclusions The CIA study in rats indicates that the MTX prodrug ROS101 may be efficacious for the treatment of RA at an equimolar dose compared to MTX, while avoiding adverse effects known to restrict treatment with MTX. Acknowledgements C.A. Hansen, co-founder of ROS Therapeutics. Disclosure of Interest V. Previtali: None declared, N. Woodworth: None declared, M. Hopkins: None declared, J. Petersen Shareholder of: ROS Therapeutics, Consultant for: ROS Therapeutics, I. Ahnfelt-Ronne Shareholder of: ROS Therapeutics, Consultant for: ROS Therapeutics, M. Clausen Shareholder of: ROS Therapeutics. |
