ABSTRACT
BACKGROUND: The clinical efficacy of combination therapy comprising a long acting beta(2)-agonist (LABA) and corticosteroid is widely recognized for the treatment of adult asthma. Here we examine the effect of salmeterol xinafoate (SX) and fluticasone propionate (FP) alone and in combination on the immunological activation of human cultured mast cells (HCMC)in vitro. METHODS: HCMC were passively sensitized with IgE antibody and then activated by challenging with anti-IgE antibody. The effect of drugs on the activation of mast cells was examined by measuring the amount of released chemical mediators (histamine, leukotrienes (LT) and prostaglandin D(2) (PGD(2))) and granulocyte macrophage colony stimulating factor (GM-CSF). RESULTS: The release of each chemical mediator was inhibited by 10-9-10-8M SX but not by 10-10-10-7M FP. The production of GM-CSF was inhibited by a concentration of 10-8M in both drugs and the inhibition was augmented by combined treatment with 10-11M of each drug. CONCLUSIONS: The immunological release of chemical mediators (histamine, LT, PGD(2)) from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Albuterol/analogs & derivatives , Androstadienes/pharmacology , Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Histamine Release/drug effects , Mast Cells/drug effects , Albuterol/administration & dosage , Albuterol/pharmacology , Androstadienes/administration & dosage , Anti-Asthmatic Agents/administration & dosage , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Dose-Response Relationship, Drug , Dose-Response Relationship, Immunologic , Drug Evaluation, Preclinical , Drug Synergism , Fluticasone , Humans , Immunoglobulin E/immunology , Leukotrienes/metabolism , Mast Cells/metabolism , Prostaglandin D2/metabolism , Salmeterol XinafoateABSTRACT
Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in blood vessel walls, normal cartilage and synovial fluid and may be important for the antioxidant capability of these tissues. We have reported that EC-SOD gene transferred mice exhibited significant suppression of clinical symptoms of type II collagen induced arthritis [Iyama, et al., Arthritis Rheum., 44, 2160-2167 (2001)] and plasma EC-SOD levels in type 2 diabetic patients were significantly negatively related to indices of insulin resistance [Adachi, et al., J. Endocrinol., 181, 413-417 (2004)]. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathological conditions of the above diseases and is a major therapeutic target, based on clinical studies with anti-TNF-alpha monoclonal antibodies such as infliximab. In this report, we investigated the effect of TNF-alpha on the expression of EC-SOD in cultured cells and the cooperating effect of infliximab. In the in vitro assays examined, expression of EC-SOD, but not other SOD isozymes, in smooth muscle and fibroblast cells were suppressed by the addition of TNF-alpha. Simultaneous addition of infliximab dose-dependently and significantly prevented the suppressive effects of TNF-alpha. p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, prevented significantly the suppressive effect of TNF-alpha suggesting that p38 MAPK is an important signaling molecule downstream of TNF-alpha to inhibit the EC-SOD expression. From the results, it is speculated that the decline in TNF-alpha activity by the administration of infliximab results in the liberation of EC-SOD from the suppressed state of gene expression. This reveals a potential usefulness of infliximab on TNF-alpha related pathological conditions such as arthritis and insulin resistance.
Subject(s)
Antibodies, Monoclonal/pharmacology , Superoxide Dismutase/genetics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Cells, Cultured , Humans , Infliximab , RNA, Messenger/analysis , p38 Mitogen-Activated Protein Kinases/physiologyABSTRACT
Hepatic dysfunction due to flutamide administration has been reported and this side effect often limits the use of the agent. The prediction of flutamide-induced hepatotoxicity is attributed to the proper use of the antiandrogen. In this study, we investigated whether hepatic dysfunction could be assessed by the metabolite profile in serum from patients receiving this drug. Serum samples were obtained from 15 patients with prostate cancer, 12 patients with no sign of hepatotoxicity and 3 patients with slight hepatic dysfunction during long-term flutamide treatment. We analyzed the metabolite profiles by LC/MS in selected ion monitoring mode and detected a new metabolite (M3) that was an oxidation product of flutamide. However, there were no consistent differences in the serum flutamide metabolites between patients with normal function and those suffering hepatic dysfunction. The metabolite profiles in the beta-glucuronidase-treated serum showed a similar pattern between normal functioning and dysfunctional groups. Thus, the profile of flutamide metabolites determined in serum may not contribute to the risk prediction of flutamide-related hepatotoxicity.
