Comparative study of glucocorticoids, cyclosporine A, and JTE-607 [(-)-Ethyl-N[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride] in a mouse septic shock model.
Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)-ethyl-N-[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-gamma, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.
Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Japan. hiroyuki.iwamura@ims.jti.co.jp
Hiroyuki
H
Iwamura
Motohide
M
Sato
Korekiyo
K
Wakitani
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D010976:Platelet Count; D011239:Prednisolone / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C468268:JTE 607; D010879:Piperazines; D010649:Phenylalanine; D016572:Cyclosporine; D011239:Prednisolone; D009195:Peroxidase