Small vessel vasculitis is a life-threatening condition, and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage; the latter being driven, in large part, by myeloperoxidase (MPO). PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is a selective 2-thiouracil mechanism-based MPO inhibitor. In this study, a pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti–glomerular basement membrane disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. These studies showed that MPO activity is critical in driving immune-complex vasculitis and provides confidence in testing the hypothesis in the clinic.
See article at J Pharmacol Exp Ther 2015, 353:288–298.
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