Reduction of urinary albumin excretion by thromboxane synthetase inhibitor, OKY-046, through modulating renal prostaglandins in patients with diabetic nephropathy

We evaluated the effects of thromboxane synthetase inhibitor, OKY-046, on urinary albumin and prostaglandin (PG) excretion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM).

Urinary excretion of 6-keto-PGF₁ (a stable metabolite of PGI₂), TXB₂ (a stable metabolite of TXA₂) and PGE₂ in NIDDM patients was comparable with that in control subjects. However, the urinary 6-keto-PGF₁/TXB₂ ratio in NIDDM patients with both micro- and macroalbuminuria was significantly (P < 0.001) lower than that in the controls.

By a single administration of OKY-046 (40 mg, i.v.) to the diabetic patients, urinary TXB₂ excretion significantly (P < 0.05) decreased from 169.7 ± 23.9 to 140.2 ± 17.9 ng/gCr, but urinary 6-keto-PGF₁ and PGE₂ excretion did not change significantly. The urinary 6-keto-PGF₁/TXB₂ ratio thus significantly (P < 0.01) increased from 1.02 ± 0.13 to 1.73 ± 0.41 as associated with significant increments in urine volume (P < 0.05), urinary sodium excretion (P < 0.01) and creatinine clearance (P < 0.05).

Of 14 diabetic patients, 7 with macroalbuminuria (albumin index exceeding 100 mg/gCr) were orally given OKY-046 (600 mg/day) for 8 weeks. After this period, the urinary albumin index significantly (P < 0.05) decreased from 524.9 ± 149.6 to 317.6 ± 90.6 mg/gCr. Urinary PG excretion did not change significantly, although the urinary 6-keto-PGF₁/TXB₂ ratio significantly (P < 0.01) increased from 1.33 ± 0.16 to 2.42 ± 0.65 and decreased to 1.09 ± 0.15 (P < 0.01) following termination of this drug. Similarly, creatinine clearance significantly (P < 0.01) increased, from 56.3 ± 14.1 to 69.4 ± 15.1 ml/min. During the period of 8 weeks, no significant alteration occurred in systemic blood pressure or glycemic control.

In conclusion, OKY-046 has a beneficial effect on albuminuria in diabetic nephropathy by modulating altered renal PGs synthesis, which leads to a change in renal hemodynamics.