TRIAL OF BUTYRATE IN BETA GLOBIN DISORDERS

丁酸盐治疗β珠蛋白疾病的试验

• 批准号: 7379532
• 负责人: SUSAN Park PERRINE
• 金额: $ 0.15万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379532
• 关键词: TRIAL; BUTYRATE; BETA; GLOBIN; DISORDERS

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. The experimental design is to administer different doses of Butyrate on an intra-patient, dose escalation schedule and to analyze Hb F production (through measurement of F-cells, F-reticulocytes, globin chain synthesis ratios, Hb F, globin mRNA), and hematologic tests, to determine an effective regimen for the individual patient. The latter tests include CBCs, differentials, reticulocyte counts, plasma free hemoglobin, proportions of irreversibly sickled cells, and globin chain electrophoresis. Chemistry panels and urinalyses will be followed to monitor for side effects. Drug levels are measured in plasma and urine. Optimal globin chain ratios are expected at 24-48 hours after dose, but have persisted for 7-10 days in some thalassemia patients. After a correction or a significant improvement in globin chain ratio or fetal globin synthesis is detected, that dose will be continued and blood drawings will be decreased in frequency. If biochemical responses are not detected, hematologic improvement can not be expected to follow. Accordingly, patients will not be continued on study, if stimulation of Hb F by at least one parameter is not detected after a maximal administered dose of 2000 mg/kg. Infusion rates will be adjusted to deliver the desired total dose at a rate tailored to avoid side effects such as nausea and headache and suppression of hemoglobin synthesis thought to be induced by excessively high plasma levels of the drug. Doses will be infused over 4 to 18 hours, at a rate not to exceed 85 mg/kg/hour. Drug will be given from 1 to 4 days per week, followed by at least 5-14 days without drug, while the patient's blood is sampled and tested. Intervals between drug treatments may be extended beyond 14 days, in order to determine how long the drug effect lasts and how often therapy is really needed once Hb F inverses. After an effective dose for a given patient is identified at the biochemical level, and a rise in total hemoglobin or a decrease in post-transfusion hemoglobin nadir is observed, the frequency of blood testing will be decreased to 4 times/ month.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。实验设计是根据患者体内不同剂量的丁酸盐，按剂量递增计划给药，并分析Hb F产生(通过测量F细胞、F网织红细胞、珠蛋白链合成比率、Hb F、珠蛋白mRNA)和血液学测试，以确定针对单个患者的有效方案。后一项测试包括CBCs、分化、网织红细胞计数、血浆游离血红蛋白、不可逆的镰状细胞比例和珠蛋白链电泳法。将跟踪化学仪表板和尿液分析，以监测副作用。药物水平是在血浆和尿液中测量的。最佳的珠蛋白链比例是在服药后24-48小时，但在一些地中海贫血患者中持续了7-10天。在检测到珠蛋白链比率或胎儿珠蛋白合成得到纠正或显著改善后，该剂量将继续，抽血频率将减少。如果没有检测到生化反应，血液学的改善就不可能随之而来。因此，如果在最大给药剂量为2000 mg/kg后，没有检测到至少一个参数对Hb F的刺激，患者将不再继续研究。输液速度将被调整，以提供所需的总剂量，其速度是量身定做的，以避免副作用，如恶心和头痛，以及被认为是由过高的血浆药物水平引起的血红蛋白合成抑制。剂量将在4至18小时内输注，速度不超过85毫克/公斤/小时。每周给药1至4天，然后至少5至14天不用药，同时对患者的血液进行采样和检测。两次药物治疗的间隔可能会延长到14天以上，以确定药物效果持续多长时间，以及一旦Hb F逆转，真正需要治疗的频率。在生化水平确定了患者的有效剂量，并观察到总血红蛋白上升或输血后血红蛋白最低值下降后，验血频率将减少到每月4次。