Koukichi Harada

In vitro effects of E3040, a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, on eicosanoid production

In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.

Inhibitory effects of a novel PAF antagonist E6123 on anaphylactic responses in passively and actively sensitized guinea pigs and passively sensitized mice

The effects of the platelet-activating factor (PAF) antagonist, E6123, on anaphylactic responses in guinea pigs and mice were investigated. E6123 inhibited i.v. antigen (Ag)- or inhaled Ag-induced bronchoconstriction in passively and actively sensitized guinea pigs after oral administration at 3 and 10 micrograms/kg, respectively. E6123 inhibited Ag inhalation-induced airway hyperreactivity in guinea pigs after oral administration at 30 micrograms/kg. E6123 protected mice from anaphylactic death with an ED50 value (p.o.) of 7 micrograms/kg. The inhibitory effects of E6123 described above were very potent compared to those of the PAF-antagonists WEB2347 and Y-24180. The present results suggest that E6123 may be beneficial for the treatment of asthma, a condition in which PAF is assumed to be involved.

Effects of a novel PAF antagonist, E6123, on passive anaphylaxis

E6123 inhibited antigen-induced bronchoconstriction, the development of bronchial hyperreactivity and eosinophil infiltration in the airway in passively sensitized guinea pigs and protected mice from anaphylactic death. The inhibitory effects of E6123 on anaphylactic response were very potent compared with those of WEB 2347 and Y-24180.

Effects of a novel PAF antagonist, E6123, on PAF-indnced biological responses

E6123 is a new member of the benzodiazepine class of PAF antagonists. Although it has similar activity in vitro to the two representative antagonists WEB2347 and Y24180, in vivo it is far more active than these compounds. Thus E6123 was effective in inhibiting dose-dependently PAF-induced bronchoconstriction when administered orally or intravenously (IC50 1.0 and 1.3 micrograms/Kg, respectively, at 3 hr), and had a minimum effective dose of 10 micrograms/Kg and 3 micrograms/Kg, respectively, against PAF-induced hematoconcentration and edema at 3 hr after oral administration. Furthermore, E6123 protects mice from PAF-induced death dose-dependently (ED50 7 micrograms/Kg at 3 hr). In conclusion, E6123 should prove valuable in pharmacological and clinical research into the roles of PAF, and in therapy of diseases such as asthma, in which PAF is assumed to play a pathological role.