Treatment with an adenosine uptake inhibitor attenuates glomerulonephritis in mice.
This study evaluated the effects of KF24345 (3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride), a novel adenosine uptake inhibitor, on experimental glomerulonephritis induced in mice by two intravenous injections of rabbit anti-mouse glomerular basement membrane antiserum. Mice with glomerulonephritis showed continuous proteinuria and the histological evaluation revealed glomerular and tubular damage at 7 weeks after the first antiserum injection. KF24345 as well as prednisolone and cyclophosphamide significantly inhibited proteinuria and glomerular damage when it was orally administered once a day from 2 to 7 weeks. Prednisolone elevated plasma bilirubin and glutamic-pyruvic transaminase levels, and cyclophosphamide decreased erythrocytes. Moreover, both prednisolone and cyclophosphamide decreased spleen and thymus weights. KF24345 did not show this kind of side effects. These results demonstrate that KF24345 ameliorates glomerulonephritis with minimal side effects in mice, suggesting that the adenosine uptake inhibitor may be useful for the treatment of glomerulonephritis.
Noji
Tohru
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan. tohru.noji@kyowa.co.jp
Sato
Hitoshi
H
Sano
Jun-ichi
J
Nishikawa
Satoshi
S
Kusaka
Hideaki
H
Karasawa
Akira
A
D000241:Adenosine / Q000378:metabolism*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D003520:Cyclophosphamide / Q000627:therapeutic use; D004906:Erythrocyte Count; D005920:Glomerular Mesangium / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D010503:Periodic Acid-Schiff Reaction; D011239:Prednisolone / Q000627:therapeutic use; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D011817:Rabbits; D013154:Spleen / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects
C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D014179:Neurotransmitter Uptake Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D003520:Cyclophosphamide; D011239:Prednisolone; D000410:Alanine Transaminase; D000241:Adenosine; D001663:Bilirubin