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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。实验设计是按照患者内剂量递增方案给予不同剂量的丁酸盐，并分析Hb F产生（通过测量F细胞、F网织红细胞、球蛋白链合成比、Hb F、球蛋白mRNA）和血液学检查，以确定个体患者的有效方案。后一项检查包括CBC、分类、网织红细胞计数、血浆游离血红蛋白、不可逆镰状细胞比例和珠蛋白链电泳。将随访生化检查和尿分析，以监测副作用。在血浆和尿液中测量药物水平。最佳珠蛋白链比预计在给药后24-48小时，但在一些地中海贫血患者中持续7-10天。在检测到珠蛋白链比或胎儿珠蛋白合成的校正或显著改善后，将继续该剂量，并降低抽血频率。 如果未检测到生化反应，则不能预期随后血液学改善。因此，如果在2000 mg/kg最大给药剂量后未检测到至少一个参数对Hb F的刺激，则患者将无法继续参与研究。 将调整输注速率，以便以定制的速率递送所需的总剂量，以避免副作用，如恶心和头痛以及血红蛋白合成抑制，这些副作用被认为是由过高的药物血浆水平诱导的。将在4至18小时内输注剂量，输注速率不超过85 mg/kg/h。每周给药1 - 4天，随后至少停药5-14天，同时对患者的血液进行采样和检测。药物治疗之间的间隔可以延长到14天以上，以确定药物作用持续多久以及一旦Hb F逆转，真正需要治疗的频率。在生化水平确定给定患者的有效剂量后，观察到总血红蛋白升高或输血后血红蛋白最低值降低，血液检测频率将降至4次/月。