Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia
Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia
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DOI：
10.1046/j.1365-2141.1996.d01-1744.x
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发表时间：
1996-06-01
影响因子：
6.5
通讯作者：
Bellingham, AJ
中科院分区：
文献类型：
--
作者：
Arya, R;Rolan, PE;Bellingham, AJ
镰状细胞的主要病理生理事件是脱氧血红蛋白S. Tucaresol （589C80；4[2-甲酰基-3-羟基苯氧甲基]苯甲酸）的细胞内聚合，这是一种取代的苯甲醛，被设计用于与血红蛋白相互作用以增加氧亲和力，并已被证明在体外抑制镰状细胞。我们给镰状细胞患者稳定用药图卡sol，观察其体内抗镰状细胞的作用。口服剂量的tucaresol或安慰剂给九稳定镰状细胞患者(17-39岁;tucaresol,六,安慰剂,3)10 d。前两个病人tucaresol被安排接受负荷剂量800毫克和1200毫克(取决于体重)第一4 d,其次是维护200或300毫克的剂量在接下来的6 d。由于担心在一个病人血细胞压积的大幅上升,随后军团收到整个剂量300毫克每日tucaresol时期。在所有接受图卡sol治疗的患者中，血红蛋白S的氧亲和力都增加了，根据剂量的不同，有10%到24%的血红蛋白发生了改变。在所有使用图卡sol的患者中，溶血减少，血红蛋白升高0.9 - 3.7 g/dl（平均2.2 g/dl），乳酸脱氢酶下降16-52%，不可逆镰状细胞计数减半。这些效果在几天内明显，并在停药后持续1-2周。图卡索拉组6例患者中有3例出现发热和颈淋巴肿大，发病时间为用药后第7天至第11天。进一步评估图卡sol对镰状细胞患者的耐受性和疗效是必要的。
The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tucaresol to sickle cell patients in the steady state to examine the anti-sickling effect in vivo. Oral doses of tucaresol or placebo were given to nine stable sickle cell patients (aged 17-39 years; tucaresol, six; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 or 300 mg for the next 6 d. Due to concerns over the sharp rise in haematocrit in one patient, subsequent cohorts received 300 mg tucaresol daily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patients on tucaresol, haemolysis was reduced with rises in haemoglobin of 0.9 - 3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16-52%, and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1-2 weeks following discontinuation of the drug. Three of the six patients on tucaresol developed fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.