Abstract：
The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.
摘要：
1-谷氨酰胺用于治疗镰状细胞病(SCD)的作用机制尚未被很好地理解,并且没有经过验证的临床生物标志物来评估应答。我们进行了为期三周的活动，谷氨酰胺的剂量递增试验和测量药代动力学（PK）暴露参数，峰浓度(Cmax)和曲线下面积(AUC)。我们使用一组生物标志物来研究谷氨酰胺的药效学(PD)并研究PK-PD关系。血浆中没有谷氨酰胺的积累,谷氨酸,随着时间的推移，精氨酸或其他氨基酸，但观察到精氨酸生物利用度略有改善。在按剂量水平随时间变化的标准分析中，对血细胞计数没有可测量的影响，粘度,ektacytometry或活性氧（ROS）。在PK-PD分析中，然而,更高的谷氨酰胺暴露（Cmax或AUC）与全血黏度增加和细胞脱水相关，还有更高的血红蛋白浓度，血细胞比容与粘度之比增加，减少网织红细胞ROS，改善红细胞变形能力，减少镰状点。这种新颖的PK-PD分析确定了生物标志物，反映了谷氨酰胺的积极和消极作用，有助于阐明其在SCD中的作用机制。应研究PK优化的剂量以实现与有益生物学效应相关的谷氨酰胺暴露（AUC或Cmax），以支持其治疗用途。
