Effects of thromboxane synthase inhibition with CGS 13080 in human cyclosporine nephrotoxicity.
Cyclosporine is a potent immunosuppressive agent, however, its use is limited by nephrotoxicity. Increased production of the potent vasoconstrictor thromboxane A2 contributes to cyclosporine nephrotoxicity in animal models, but the role of thromboxane in human cyclosporine nephrotoxicity has not been established. We therefore studied cyclosporine-treated renal allograft recipients who had evidence of toxicity manifested by decreased renal function. We measured GFR and PAH clearance (CPAH) before, during, and one week after a 48-hour intravenous infusion of the thromboxane synthase inhibitor CGS 13080. At baseline, the urinary excretion of TXB2 and 2,3-dinor-TXB2 was elevated in the study patients compared to healthy subjects. CGS 13080 infusion caused selective and nearly complete inhibition of thromboxane metabolite excretion in all patients. Mean CPAH improved 33% from 223 +/- 45 to 298 +/- 59 ml/min/m2 (P = 0.055) during infusion, while mean GFR improved 9% from 50.1 +/- 3.9 at baseline to 54.6 +/- 4.5 ml/min/1.73 m2 (P = 0.111). The effect on GFR occurred primarily in those patients taking calcium channel blockers. The mean increase in GFR in these 5 patients was 10.0 +/- 2.8 versus -1.0 +/- 2.8 ml/min/m2 in the remainder. We conclude that thromboxane synthase inhibitors may be useful in attenuating the nephrotoxic effects of cyclosporine following renal transplantation.
Smith
S R
SR
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Creech
E A
EA
Schaffer
A V
AV
Martin
L L
LL
Rakhit
A
A
Douglas
F L
FL
Klotman
P E
PE
Coffman
T M
TM
D000328:Adult; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000378:metabolism
D007093:Imidazoles; D011725:Pyridines; D013931:Thromboxanes; D016572:Cyclosporine; C037787:pirmagrel; D013930:Thromboxane-A Synthase