GT4P COMPARED TO SODIUM PHENYLBUTYRATE IN UREA CYCLE DISORDERS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尿素循环障碍（UCD）代表一组遗传性疾病，其通常在新生儿时期以血氨水平升高（高氨血症）灾难性地呈现，并且由于必需尿素循环酶的缺乏或缺乏而具有高死亡率和发病率。目前的药物治疗包括使用苯丁酸盐（PBA）（Buphenyl）替代途径治疗来补充氮，并补充氨基酸L瓜氨酸或L-精氨酸。Buphenyl必须以大剂量施用，并且具有不良味道、钠含量和气味的并发症。GT 4P是Buphenyl的前体药物，预计将提供类似的氮清除能力，同时消除与药物相关的当前问题。 为了进一步评价GT 4P作为Buphenyl替代品的安全性和耐受性，这将是一项II期、开放标签、转换剂量递增研究。 对于目前正在接受Buphenyl治疗的患者，GT 4P将逐步引入，而Buphenyl将逐步停用，然后将转换回Buphenyl。在GT 4P过渡期间，将密切监测患者的高氨血症，并将进行一些安全性实验室检查。 先前的一项临床研究的结果表明，GT 4P是安全的，耐受性良好，可能是患者及其护理人员的首选。希望这项研究的结果是有利的，下一步将是III期疗效研究，并进一步建立GT 4P作为UCD患者Buphenyl的替代疗法。 假设：GT 4P作为UCD治疗与Buphenyl一样安全且更耐受。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urea Cycle Disorders (UCD's) represent a group of inherited diseases that usually present catastrophically with elevations of blood ammonia levels (hyerammonemia) in the newborn period and have a high mortality and morbidity due toa deficiency in or lack of an essential urea cycle enzyme. Current pharmacological treatment involves the use of alternative pathway therapy with phenylbutyrate (PBA) (Buphenyl¿) to scavenge nitrogen, combined with supplementation of the amino acids L citrulline or L-arginine. Buphenyl must be administered in large doses and has the complications of bad taste, sodium content and odor. GT4P is a pro-drug of Buphenyl, and is expected to provide similar nitrogen-scavenging abilities while eliminating the current issues associated with the drug. To further evaluate the safety and tolerabilty of GT4P as a replacement for Buphenyl, this will be a phase II, open-label, switch-over dose escalation study. For patients currently on Buphenyl, GT4P will be gradually phased in while Buphenyl is phased out, and then a switch will be made back to Buphenyl. Patients will be closely monitored for hyperammonemia during the transition to and from GT4P and a number of safety lab tests will be conducted. Results from the one previous clinical study indicate that GT4P will be safe and well tolerated and may be preferred by patients and their caregivers. Hopefully, with favorable results from this study, the next step will be phase III efficacy studies and the further establishment of GT4P as an alternative therapy to Buphenyl in patients with UCDs. Hypothesis: GT4P will be as safe and more tolerable than Buphenyl as a UCD treatment.