Reduction of chronic ciclosporin nephrotoxicity by thromboxane synthase inhibition with OKY-046

Kidney & Blood Pressure Research
Y J KimH K Moon

Abstract

Ciclosporin A (CsA) is a potent immunosuppressive agent which is extremely effective in controlling allograft rejection and in the treatment of autoimmune disease and nephrotic syndrome. Unfortunately, its use is limited by chronic, irreversible nephrotoxicity. Administration of CsA induces renal vasoconstriction, causing a reduction in renal blood flow. An alteration of the prostaglandin-thromboxane cascade may be involved in the vasoconstriction. We studied the role of thromboxane A2 in CsA nephrotoxicity and the ability of a thromboxane synthase inhibitor, OKY-046, to reduce the CsA nephrotoxicity. Daily administration of CsA 25 mg/kg for 28 days to Sprague-Dawley rats resulted in increased excretion of urinary thomboxane B2 (47.9+/-11.5 vs. 27.2+/-9.7 ng/24 h; p<0.05) and decreased creatinine clearance (0.25+/-0.07 vs. 0.43+/-0.17ml/min/100 g; p<0.01) as compared with administration of vehicle only. Histologically, large numbers of lysosomes in the tubular epithelium were characteristic. Coadministration of OKY-046 prevented both the rise in urinary thromboxane B2 excretion (40.0+/-11.8 ng/24 h) and the reduction in the creatinine clearance (0.44+/-0.11 ml/min/100 g). The severity of the histological changes was significant...Continue Reading

Citations

Sep 10, 2002·Current Hypertension Reports·John J Curtis
Aug 8, 2008·American Journal of Physiology. Renal Physiology·Helene FrancoisThomas M Coffman
Feb 18, 2004·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·David A BaranAlan L Gass
Jan 8, 2005·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Rita RezzaniRossella Bianchi

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