ABSTRACT
Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.
Subject(s)
Arthritis, Experimental/therapy , Immunotherapy/methods , Macrophages/drug effects , Neutrophils/drug effects , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Rheumatic Fever/therapy , Animals , Antibodies, Blocking/administration & dosage , Antibodies, Monoclonal/administration & dosage , Arthritis, Experimental/immunology , Cell Movement/drug effects , Clinical Trials as Topic , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Humans , Inflammation Mediators/metabolism , Macrophages/immunology , Male , Mice , Mice, Inbred DBA , Neutrophils/immunology , Receptor, Anaphylatoxin C5a/immunology , Rheumatic Fever/immunologyABSTRACT
BACKGROUND: Mortality of mothers and newborns is an important public health problem in low-income countries. In the rural setting, implementation of community based education and mobilization are strategies that have sought to reduce these mortalities. Frequently such approaches rely on volunteers within each community. OBJECTIVE: To assess the perceptions of the community volunteers in rural Kenya as they implemented the EmONC program and to identify the incentives that could result in their sustained engagement in the project. METHOD: A community-based cross sectional survey was administered to all volunteers involved in the study. Data were collected using a self-administered supervision tool from all the 881 volunteers. RESULTS: 881 surveys were completed. 769 respondents requested some form of incentive; 200 (26%) were for monetary allowance, 149 (19.4%) were for a bicycle to be used for transportation, 119 (15.5%) were for uniforms for identification, 88 (11.4%) were for provision of training materials, 81(10.5%) were for training in Home based Life Saving Skills (HBLSS), 57(7.4%) were for provision of first AID kits, and 39(5%) were for provision of training more facilitators, 36(4.7%) were for provision of free medication. CONCLUSION: Monetary allowances, improved transportation and some sort of identification are the main incentives cited by the respondents in this context.
