Improvement of renal function with a selective thromboxane A2 synthetase inhibitor, DP-1904, in lupus nephritis.
OBJECTIVE
To examine abnormalities of prostanoid metabolism in lupus nephritis, which may affect renal function, and the effects of 4 day dosing of a selective thromboxane A2 (TXA2) synthetase inhibitor, DP-1904, on prostanoid metabolism.


METHODS
Urinary levels of various prostanoids, thromboxane B2(TXB2), 11-dehydro-TXB2, 6-keto-prostaglandin F1 alpha, 2,3-dinor-6-keto-PGF1 alpha, and prostaglandin E2 were determined. In a randomized crossover study, 8 patients with biopsy proven lupus nephritis were given 4 days' oral administration of DP-1904 (400 mg/day bid) or indomethacin (50 mg/day bid). The effects of DP-1904 on prostanoid metabolism were studied.


RESULTS
Urinary excretion of TXB2, which reflects the renal production of TXA2, was significantly increased in patients with lupus nephritis compared with non-renal systemic lupus erythematosus (SLE)(p < 0.05); enhanced production of TXA2 was also estimated in patients with lupus nephritis. The urinary TXB2/6-keto-PGF1 alpha ratio was also increased in lupus nephritis compared with non-renal SLE (p < 0.01), indicating a prostanoid imbalance that may lead to impaired renal function and subsequent pathology. During administration of DP-1904, the urinary excretion of TXB2 was significantly decreased after 1 to 2 days. An increase in creatinine clearance as a measure of renal function was observed. In contrast, during the administration of indomethacin, urinary excretion of both TXB2 and 6-keto-PGF1 alpha decreased and there were no significant changes in the urinary TXB2/6-keto-PGF1 alpha ratio or creatinine clearance. Hemodynamic changes were associated with a slight increase in sodium excretion, but with no change in arterial blood pressure. No side effects were elicited during the 4 days of treatments.


CONCLUSIONS
The abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function, which was mediated hemodynamically, and the altered metabolism was reversible and at least partially corrected by a TXA2 synthetase inhibitor, DP-1904.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
T
T
Yoshida
H
H
Kameda
Y
Y
Ichikawa
T
T
Tojo
M
M
Homma
D000328:Adult; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007213:Indomethacin / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism*; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000378:metabolism*; D008875:Middle Aged; D011453:Prostaglandins / Q000378:metabolism* / Q000652:urine; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011453:Prostaglandins; D013764:Tetrahydronaphthalenes; D013928:Thromboxane A2; C056295:nafagrel; D013930:Thromboxane-A Synthase; D007213:Indomethacin