Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model.
Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model.
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DOI：
10.1016/j.urology.2014.07.043
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发表时间：
2014-11
期刊：
影响因子：
2.1
通讯作者：
Tischfield JA
中科院分区：
文献类型：
--
作者：
Sahota A;Parihar JS;Capaccione KM;Yang M;Noll K;Gordon D;Reimer D;Yang I;Buckley BT;Polunas M;Reuhl KR;Lewis MR;Ward MD;Goldfarb DS;Tischfield JA
评估L-胱氨酸二甲酯（CDME）（一种胱氨酸晶体生长抑制剂）治疗Slc 3a 1基因敲除小鼠胱氨酸尿症模型中胱氨酸尿石症的有效性。每天通过管饲法递送CDME（每只小鼠200 μg）或水，持续四周。通过灌胃或供水给予较高剂量，以评估器官毒性。使用几种分析方法分析尿氨基酸和胱氨酸结石以评估药物疗效。与水组相比，CDME治疗导致结石尺寸显著减小（p = 0.0002），但结石数量更多（p = 0.005）。通过微型计算机断层扫描，两组之间结石大小分布的变化很明显。总体而言，两组之间尿液中的胱氨酸排泄量相同（p = 0.23），表明CDME不会干扰胱氨酸代谢。CDME组胱氨酸结石的SEM分析显示晶体习性发生变化，出现大量小晶体。通过UPLC-MS仅在CDME组的结石中检测到L-半胱氨酸甲酯，表明CDME代谢产物被掺入晶体结构中。在试验剂量下未观察到病理学变化。这些数据表明，CDME促进小结石的形成，但不阻止结石形成，与CDME抑制胱氨酸晶体生长的假设一致。结合缺乏观察到的不良反应，我们的研究结果支持使用CDME作为一种可行的治疗胱氨酸尿石症。
To assess the effectiveness of L-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in a Slc3a1 knockout mouse model of cystinuria. CDME (200 μg per mouse) or water was delivered by gavage daily for four weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical methods. Treatment with CDME led to a significant decrease in stone size compared with the water group (p = 0.0002), but the number of stones was greater (p = 0.005). The change in stone size distribution between the two groups was evident by micro computed tomography. Overall, cystine excretion in urine was the same between the two groups (p = 0.23), indicating that CDME did not interfere with cystine metabolism. SEM analysis of cystine stones from the CDME group demonstrated a change in crystal habit, with numerous small crystals. L-cysteine methyl ester was detected by UPLC-MS in stones from the CDME group only, indicating that a CDME metabolite was incorporated into the crystal structure. No pathological changes were observed at the doses tested. These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.
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影响因子：
3.7
作者：
Eggermann T;Venghaus A;Zerres K
通讯作者：
Zerres K
LRTAE：存在表型和/或基因型错误分类错误时，遗传关联与病例/控制数据的统计能力提高。
影响因子：
2.9
作者：
Barral, Sandra;Haynes, Chad;Stone, Millicent;Gordon, Derek
通讯作者：
Gordon, Derek
影响因子：
1.6
作者：
Schwentner, C;Oswald, J;Radmayr, C
通讯作者：
Radmayr, C
影响因子：
3.5
作者：
Feliubadaló, L;Arbonés, ML;Nunes, V
通讯作者：
Nunes, V
DOI：
10.2215/cjn.00320111
发表时间：
2011-08-01
影响因子：
9.8
作者：
Goldfarb, David S.
通讯作者：
Goldfarb, David S.