EFFECT OF DP-1904, A THROMBOXANE A(2) SYNTHASE INHIBITOR, ADMINISTERED FROM THE AUTOLOGOUS PHASE ON CRESCENTIC-TYPE ANTI-GEM NEPHRITIS IN RATS

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7, 8-t etrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane ( TX) A(2) synthase inhibitor, was compared with that of OKY-046 and aza thioprine, using an experimental model of nephritis, crescentic-type a nti-glomerular basement membrane (GEM) nephritis. Test drugs were give n p.o. once daily from an autologous phase in which proteinuria was al ready fully developed. DP-1904 (15 and 45 mg/kg per day) and OKY-046 ( 20 mg/kg per day), another TXA2 synthase inhibitor, significantly inhi bited the development of glomerular alteration as well as the elevatio n of proteinuria. On the other hand, azathioprine (20 mg/kg per day), an immunosuppressive agent, failed to suppress the proteinuria. A sing le administration of DP-1904 or OKY-046 inhibited glomerular TXB(2) pr oduction and increased glomerular prostaglandin (PG) E(2) and 6-keto P GF(1 alpha) production in nephritic rats. Both drugs apparently decrea sed the depositions of both rabbit immunoglobulin (Ig)G and rat IgG on GEM in nephritic rats, but azathioprine inhibited only the deposition of rat IgG. These results suggest that DP-1904 may be an effective ag ent for the treatment of proliferative glomerulonephritis and its anti nephritic effect may be due to the amelioration of abnormal metabolism of arachidonic acid.