Gladue R P, Newborg M F
Pfizer, Inc., Groton, Connecticut 06340.
Transplantation. 1991 Nov;52(5):837-41. doi: 10.1097/00007890-199111000-00016.
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.
肾血管收缩被认为是环孢素肾毒性作用的一个主要促成因素。为了评估血栓素（Tx）的相对作用，研究了将环孢素（CsA）与选择性Tx合成酶抑制剂达美格雷（DAZ，辉瑞公司）联合使用的效果。给大鼠口服50mg/kg的DAZ加50mg/kg的CsA，并评估各种肾毒性和疗效指标。与单独用CsA治疗的动物相比，用CsA + DAZ治疗的动物肾TxB2合成恢复正常（分别为160与338pg/ml）。如N-乙酰-β-D-氨基葡萄糖苷酶（NAG）尿排泄减少（分别为9.7与14.1U/g肌酐）以及肾脏切片的组织学检查所示，联合给予DAZ的动物单独用CsA治疗后出现的近端肾小管损伤也减少。然而，在实验性变应性脑脊髓炎（EAE）模型中，DAZ不影响CsA的血药浓度及其有效活性。这些研究表明，血栓素生成增加在CsA的急性肾毒性作用中起主要作用，并证明DAZ可降低这种毒性，而不改变CsA的有效活性。
