Effect of DP-1904, a thromboxane A2 synthase inhibitor, administered from the autologous phase on crescentic-type anti-GBM nephritis in rats.
The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane (TX) A2 synthase inhibitor, was compared with that of OKY-046 and azathioprine, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane (GBM) nephritis. Test drugs were given p.o. once daily from an autologous phase in which proteinuria was already fully developed. DP-1904 (15 and 45 mg/kg per day) and OKY-046 (20 mg/kg per day), another TXA2 synthase inhibitor, significantly inhibited the development of glomerular alteration as well as the elevation of proteinuria. On the other hand, azathioprine (20 mg/kg per day), an immunosuppressive agent, failed to suppress the proteinuria. A single administration of DP-1904 or OKY-046 inhibited glomerular TXB2 production and increased glomerular prostaglandin (PG) E2 and 6-keto PGF1 alpha production in nephritic rats. Both drugs apparently decreased the depositions of both rabbit immunoglobulin (Ig) G and rat IgG on GBM in nephritic rats, but azathioprine inhibited only the deposition of rat IgG. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis and its antinephritic effect may be due to the amelioration of abnormal metabolism of arachidonic acid.
Nagao
T
T
Department of Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Nagamatsu
T
T
Suzuki
Y
Y
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D001379:Azathioprine / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D008297:Male; D008689:Methacrylates / Q000627:therapeutic use; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005719:gamma-Globulins / Q000378:metabolism
D000963:Antimetabolites; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008689:Methacrylates; D013764:Tetrahydronaphthalenes; D005719:gamma-Globulins; C056295:nafagrel; D003404:Creatinine; D013930:Thromboxane-A Synthase; C034364:ozagrel; D001379:Azathioprine