The protective effects of the thromboxane synthetase inhibitor Dazmegrel on nephrotoxicity in cyclosporine-treated rats.
Renal vasoconstriction has been implicated as a major contributing factor for the nephrotoxic effects of cyclosporine. In an attempt to assess the relative contribution of thromboxane (Tx), the effects of coadministering CsA with the selective Tx synthetase inhibitor, Dazmegrel (DAZ) (Pfizer, Inc.), were determined. Rats were treated orally with 50 mg/kg of DAZ plus 50 mg/kg of CsA and various indicators of nephrotoxicity and efficacy were assessed. Animals treated with CsA + DAZ had a normalization of renal TxB2 synthesis as compared with animals treated with CsA alone (160 vs. 338 pg/ml). Kidney proximal tubule damage following CsA treatment alone was also reduced in animals coadministered DAZ, as indicated by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) (9.7 vs. 14.1 U/g creatinine) and by histological examination of kidney sections. However, DAZ did not affect blood levels of CsA nor its efficacious activity in a model of experimental allergic encephalomyelitis (EAE). These studies suggest a major role of elevated thromboxane production in the acute nephrotoxic effects of CsA and demonstrate a reduction in this toxicity by DAZ without altering CsA's efficacious activity.
Gladue
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RP
Pfizer, Inc., Groton, Connecticut 06340.
Newborg
M F
MF
D000118:Acetylglucosaminidase / Q000652:urine; D000595:Amino Acid Sequence; D000818:Animals; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects* / Q000378:metabolism; D004336:Drug Antagonism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009404:Nephrotic Syndrome / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014665:Vasodilator Agents / Q000494:pharmacology*
D007093:Imidazoles; D014665:Vasodilator Agents; C039242:dazmegrel; D013929:Thromboxane B2; D016572:Cyclosporine; D003404:Creatinine; D000118:Acetylglucosaminidase; D013930:Thromboxane-A Synthase