OxDc-A0:一种口服胃耐受草酸脱羧酶,用于治疗继发性高草酸尿。

IF 2 2区 医学 Q2 UROLOGY & NEPHROLOGY
Hai-Feng Liu, Chun-Yan Li, Yan-Hong Liu, Qi Yao, Qing-Shan Li, Long-Jiang Yu
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引用次数: 0

摘要

继发性高草酸尿是一种获得性草酸代谢紊乱,其特征是尿中草酸排泄量增加。通过酶治疗减少外源性草酸盐的吸收是一种很有前途的治疗策略。然而,上胃肠道极酸性的pH值和富含蛋白酶的环境对口服蛋白质疗法构成了主要障碍。OxDc-A0是一种新型的胃耐受重组草酸脱羧酶,可以降解胃中的草酸,从而限制胃肠道中的草酸池,减少草酸的吸收和尿排泄。本研究旨在研究OxDc-A0的药效学、药代动力学和安全性,以评估其用药可能性。在体外和高草酸饮食诱导的高草酸尿比格犬模型中对其进行药效学评价。在高草酸尿狗模型中,OxDc-A0表现出良好的胃耐受性和显著的减少尿草酸排泄的功效。按照临床前安全性研究指南,在Sprague-Dawley大鼠、beagle犬和金仓鼠中评价OxDc-A0的安全性。口服高达37,500 U/kg的OxDc-A0对大鼠或狗的中枢神经、心血管或呼吸系统未观察到不良反应。药代动力学研究表明,OxDc-A0非全身吸收,主要分布于胃肠道。毒理学研究表明,OxDc-A0具有优异的耐受性,大鼠和狗的NOAEL均为37,500 U/kg/天。大鼠最大耐受剂量≥105,000 U/kg,犬最大耐受剂量≥87,000 U/kg。综上所述,OxDc-A0作为治疗继发性高血氧症的新候选药物具有很大的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
OxDc-A0: an oral gastro-tolerant oxalate decarboxylase for treating secondary hyperoxaluria.

Secondary hyperoxaluria is an acquired oxalate metabolic disorder characterized by increased urinary oxalate excretion. Reducing exogenous oxalate absorption through enzyme therapy represents a promising therapeutic strategy. However, the extremely acidic pH and protease-rich environment of the upper gastrointestinal tract pose major obstacles for the oral administration of protein therapeutics. OxDc-A0, a novel gastro-tolerant recombinant oxalate decarboxylase, can degrade oxalate in the stomach, thereby limiting the oxalate pool in the gastrointestinal tract and reducing oxalate absorption and urinary excretion. This study aimed to investigate the pharmacodynamics, pharmacokinetics, and safety profile of OxDc-A0 to assess its drug likeliness. The pharmacodynamics were evaluated in vitro and in hyperoxaluria beagle dog model induced by a high-oxalate diet. OxDc-A0 exhibited excellent gastric tolerance and significant efficacy in reducing urinary oxalate excretion in the dog model with hyperoxaluria. The safety of OxDc-A0 was evaluated in Sprague-Dawley rats, beagle dogs, and golden hamsters according to the guidelines for preclinical safety studies. No adverse effects were observed on the central nervous, cardiovascular, or respiratory system in rats or dogs treated orally with OxDc-A0 up to 37,500 U/kg. Pharmacokinetic studies showed that OxDc-A0 is non-systemically absorbed and is mainly distributed in the gastrointestinal tract. Toxicological studies showed that OxDc-A0 has excellent tolerance, with a NOAEL of 37,500 U/kg/day in both rats and dogs. The maximum tolerated dose was ≥ 105,000 U/kg in rats and ≥ 87,000 U/kg in dogs. Overall, OxDc-A0 shows great potential as a new drug candidate for treating secondary hyperoxaluria.

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来源期刊
Urolithiasis
Urolithiasis UROLOGY & NEPHROLOGY-
CiteScore
4.50
自引率
6.50%
发文量
74
期刊介绍: Official Journal of the International Urolithiasis Society The journal aims to publish original articles in the fields of clinical and experimental investigation only within the sphere of urolithiasis and its related areas of research. The journal covers all aspects of urolithiasis research including the diagnosis, epidemiology, pathogenesis, genetics, clinical biochemistry, open and non-invasive surgical intervention, nephrological investigation, chemistry and prophylaxis of the disorder. The Editor welcomes contributions on topics of interest to urologists, nephrologists, radiologists, clinical biochemists, epidemiologists, nutritionists, basic scientists and nurses working in that field. Contributions may be submitted as full-length articles or as rapid communications in the form of Letters to the Editor. Articles should be original and should contain important new findings from carefully conducted studies designed to produce statistically significant data. Please note that we no longer publish articles classified as Case Reports. Editorials and review articles may be published by invitation from the Editorial Board. All submissions are peer-reviewed. Through an electronic system for the submission and review of manuscripts, the Editor and Associate Editors aim to make publication accessible as quickly as possible to a large number of readers throughout the world.
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