ono-4057 and Neutropenia

Topics: Animals; Calcium; Guinea Pigs; Humans; In Vitro Techniques; Leukotriene B4; Neutropenia; Neutrophils; Phenylpropionates

Neutrophils are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, since prominent neutrophil infiltration has been observed in the inflamed colonic mucosa of patients with IBD. However, the role of neutrophils in the pathogenesis of IBD and experimental colitis remains equivocal. The aim of the present study is to clarify the possible role of neutrophils in the progression of acetic acid-induced colitis in mice.. Using neutropenic mice treated with cyclophosphamide or with an LTB4 receptor antagonist, ONO-4057, the relationship between the severity of macroscopic colonic damage, the extent of myeloperoxidase (MPO) activities in the colonic tissues, and the number of neutrophils in the blood were examined after induction of colitis in mice.. Changes of MPO activity in the colonic tissues paralleled well with the severity of the mucosal damage. In spite of a significant reduction in the number of neutrophils in the blood in cyclophosphamide-treated mice, neither the severity of mucosal damage in the colon nor the increase in MPO activities in the colonic tissues was affected 24 h after induction of colitis. Treatment with ONO-4057 significantly suppressed both the severity of mucosal damage in the colon and MPO activities in the colonic tissues in acetic acid-induced colitis in mice.. The present results, obtained using treatment with cyclophosphamide and ONO-4057, show that the severity or the progression of acetic acid-induced colitis in mice was not influenced by a reduction of circulating neutrophils to about 25% of base line.

Topics: Acetic Acid; Animals; Colitis; Colon; Cyclophosphamide; Immunosuppressive Agents; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Neutropenia; Neutrophils; Peroxidase; Phenylpropionates

ONO-4057(5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]valeric acid), an orally active leukotriene B4(LTB4) antagonist, displaced the binding of [3H] LTB4 to the LTB4 receptor in human neutrophil (Ki = 3.7 +/- 0.9 nM). ONO-4057 inhibited the LTB4-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC50) = 0.7 +/- 0.3 microM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB4 (IC50 = 3.0 +/- 0.1, 0.9 +/- 0.1 and 1.6 +/- 0.1 microM) without showing any agonist activity at concentration up to 30 microM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30 microM. In the in vivo study, ONO-4057 given orally, prevented LTB4-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED50) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB4 antagonist and may be a potential candidate for the treatment of various inflammatory diseases.

Topics: Animals; Calcium; Cell Aggregation; Chemotaxis, Leukocyte; Complement C5a; Cytoplasmic Granules; Guinea Pigs; Humans; Inflammation; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils; Phenylpropionates; Receptors, Immunologic; Receptors, Leukotriene B4; Tetradecanoylphorbol Acetate

Topics: Animals; Binding, Competitive; Cell Aggregation; Guinea Pigs; Humans; Leukotriene B4; Lung; Muscle Contraction; Muscle, Smooth; Neutropenia; Neutrophils; Peroxidase; Phenylpropionates; Rats; Receptors, Immunologic; Receptors, Leukotriene B4; Skin