Voxelotor (also known as GBT440) is a hemoglobin S polymerization inhibitor that increases the hemoglobin (Hb) affinity for oxygen (O₂) in blood and has been approved for the treatment of sickle cell disease (SCD). In this study, GBT1118, an analog of voxelotor, was used to assess the impact of increasing Hb affinity for O₂ on brain tissue oxygenation, blood pressure, heart rate, O₂ delivery, and tolerance to hypoxia in Townes transgenic SCD mice. Brain oxygenation and O₂ delivery were studied during normoxia and severe hypoxic challenges. GBT1118's pharmacokinetics in SCD mice allowed it to achieve the degree of Hb modification that voxelotor targets clinically. Chronic treatment with GBT1118 increased Hb affinity for O₂, reducing the PO₂ for 50% Hb O₂ saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. Chronic treatment with GBT1118 significantly improved hematological, hemodynamic, and oxygenation parameters during hypoxia, preserved cortical oxygenation during normoxia and improved cortical oxygenation during hypoxia, and increased tolerance to severe hypoxia. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O₂ in preventing the complete deoxygenation of blood and consequent RBC sickling during hypoxia in SCD.

中文翻译：

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用 GBT1118 提高血红蛋白对氧的亲和力提高镰状细胞小鼠的缺氧耐受性

Voxelotor（也称为 GBT440）是一种血红蛋白 S 聚合抑制剂，可增加血红蛋白 (Hb) 对血液中氧 (O ₂ ) 的亲和力，并已被批准用于治疗镰状细胞病 (SCD)。在这项研究中，GBT1118 是一种voxelotor 的类似物，用于评估增加 Hb 对 O ₂的亲和力对Townes 转基因 SCD 小鼠脑组织氧合、血压、心率、O _{2输送和对缺氧的耐受性的影响。}在常氧和严重缺氧挑战期间研究了脑氧合和 O _2输送。GBT1118 在 SCD 小鼠中的药代动力学使其能够达到 voxelotor 在临床上靶向的 Hb 修饰程度。GBT1118 的慢性治疗增加了对 O 的 Hb 亲和力_如图2所示，将SCD小鼠中50％Hb O ₂饱和度(P50)的PO ₂从31mmHg降低到18mmHg。GBT1118 的长期治疗显着改善了缺氧期间的血液学、血流动力学和氧合参数，在常氧期间保持了皮质氧合，在缺氧期间改善了皮质氧合，并增加了对严重缺氧的耐受性。与慢性治疗引起的血液学变化无关，单剂量的 GBT1118 显着提高了对缺氧的耐受性，突出了增加 Hb 对 O ₂的亲和力在防止 SCD 缺氧期间血液完全脱氧和随后的 RBC 镰状细胞中的益处。