Effects of thromboxane synthase inhibition with CGS 13080 in human cyclosporine nephrotoxicity

Abstract

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.

Reduction of Chronic Ciclosporin Nephrotoxicity by Thromboxane Synthase Inhibition with OKY-046

“…A decrease in renal blood flow appears to be one of the mediators of the toxic effect of CsA on the kidney [9], The precise etiology is unknown, but proposed mechanisms in-elude alterations in renal sympathetic nervous activity [2], changes in intrinsic renal vascular reactivity [3,4], and al terations in renal production of prostaglandins, especially TXA2 [5], The endothelial cell injury has been also suspect ed to be especially mediated through the thrombotic microangiopathy that occurs following CsA treatment [10].…”

Cyclosporine A Preparations and Their Vehicles Induce Contraction of the Guinea Pig Gallbladder in vitro: The Role of Cyclooxygenase Metabolites

“…Therefore, TxA 2 and PGI 2 or PGE 2 may represent a labilizing/stabilizing pair of endogenous humoral substances [25]. It has been demonstrated that administration of PGE analogues prevented or attenuated various toxic events induced by CyA [26,27], similarly TxA 2 synthase inhibitors and TxA 2 receptor antagonists were also reported to be useful in attenuating various toxic effects of CyA [28][29][30]. However, to our knowledge, there is no literature about the role of PGs in the effect of CyA preparations on the gallbladder.…”

Metabolomics Approach to Explore the Effects of Rebamipide on Inflammatory Arthritis Using Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

“…Previous in vivo studies have suggested that to target thromboxane receptor can attenuated renal injury in experimental model of lupus [35]. Also, to block thromboxane receptor and thromboxane synthesis through inhibiting thromboxane synthase can play protective roles in cyclosporine-induced nephrotoxicity in experimental model [36] and in patients with deteriorated renal allograft function [37]. Taken together, relatively high-dose of rebamipide might be translated in renal injury of which the pathogenesis of which is involved in enhanced thromboxane signal, while low-dose of rebamipide might work as anti-inflammatory and anti-oxidant drug in chronic inflammatory and degenerative diseases.…”