Atweh G F, Sutton M, Nassif I, Boosalis V, Dover G J, Wallenstein S, Wright E, McMahon L, Stamatoyannopoulos G, Faller D V, Perrine S P
Departments of Medicine, Pediatrics and Biomathematical Sciences, Mount Sinai School of Medicine, New York, NY, USA.
Blood. 1999 Mar 15;93(6):1790-7.
High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.
高水平的胎儿血红蛋白（Hb F）可预防镰状细胞病的许多并发症，并提高生存率。先前的研究表明，丁酸盐和其他短链脂肪酸可在体外红细胞和体内动物模型中增加Hb F的产生。然而，丁酸盐也已知会抑制包括红细胞在内的许多细胞类型的增殖。在动物模型和早期临床试验中使用丁酸盐的经验表明，长期高剂量使用丁酸盐后，Hb F反应可能会丧失。我们推测这种反应丧失可能是丁酸盐抗增殖作用的结果。我们设计了一种间歇性或脉冲疗法方案，即丁酸盐给药4天，然后停药10至24天。这种脉冲方案在11名患者中的9名中诱导了胎儿球蛋白基因表达。在平均持续29.9周的间歇性丁酸盐治疗后，该组的平均Hb F从7.2%增加到21.0%（P<.002）。这与F细胞和F网织红细胞数量的平行增加相关。总血红蛋白水平也从平均7.8 g/dL增加到平均8.8 g/dL（P<.006）。所有有反应者的Hb F水平升高均得以维持，包括1名接受脉冲丁酸盐治疗超过28个月的患者。该方案在本研究中超过三分之二的成年镰状细胞病患者中导致Hb F水平显著且持续升高，耐受性良好，无不良副作用。这些令人鼓舞的结果需要在更多镰状细胞病患者中进行进一步证实，并对临床结果进行适当评估。
