Dick Maurice H, Abdelgadir Arowa, Kulkarni Vaishnavi Vijaya, Akram Hamna, Chatterjee Abanti, Pokhrel Sushil, Khan Safeera
Medical School, Saint James School of Medicine, Arnos Vale, VCT.
Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Cureus. 2022 May 11;14(5):e24920. doi: 10.7759/cureus.24920. eCollection 2022 May.
Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting millions worldwide. The median life expectancy of someone with SCD remains significantly low despite improvements in standards of care and the implementation of hydroxyurea therapy. Notably, a 20-year interval existed (after the implementation of hydroxyurea therapy) prior to the approval of other sickle cell medications, namely, l-glutamine, voxelotor, and crizanlizumab. In this systematic review, these new medications' impact on the occurrences of vaso-occlusive crisis (VOC) events were analyzed and the adverse events of each were noted. Further, a secondary analysis was conducted to determine the effect of combination therapies, whether synergistic, antagonistic, or additive. The systematic review was conducted following the PRISMA 2020 guidelines. The effect-based and dose-effect-based approaches were utilized to determine the combined drugs combination index based on the recommended dosage to achieve an efficacy of 50%. L-glutamine and crizanlizumab were effective in reducing the frequency of VOC (p= 0.0216 and p = 0.02). Voxelotor effect on the reduction of VOC occurrences was not significant, however, its effect on increasing hemoglobin levels was significant (p= <0.001). In all three therapies, pain was the most common adverse event reported by participants. The analysis of combination therapies revealed that voxelotor plus l-glutamine was synergistic, voxelotor plus crizanlizumab was antagonistic, and l-glutamine plus crizanlizumab was additive. Thus, voxelotor plus l-glutamine combination therapy may be more beneficial to sickle cell disease patients. As such, robust combination drug studies for approved therapies used in SCD should be initiated with a specific focus on voxelotor plus l-glutamine. Additionally, the development of medications that lessen the pain burden in sickle cell disease patients should also be prioritized.
镰状细胞病（SCD）是一组遗传性红细胞疾病，影响着全球数百万人。尽管护理标准有所提高且实施了羟基脲疗法，但SCD患者的中位预期寿命仍然显著较低。值得注意的是，在其他镰状细胞药物（即L-谷氨酰胺、伐昔洛韦和克立唑单抗）获批之前，（在实施羟基脲疗法之后）存在20年的间隔期。在本系统评价中，分析了这些新药对血管闭塞性危机（VOC）事件发生率的影响，并记录了每种药物的不良事件。此外，进行了一项二次分析以确定联合疗法的效果，无论是协同、拮抗还是相加作用。本系统评价是按照PRISMA 2020指南进行的。基于效应和基于剂量效应的方法被用于根据推荐剂量确定联合药物的联合指数，以达到50%的疗效。L-谷氨酰胺和克立唑单抗在降低VOC频率方面有效（p = 0.0216和p = 0.02）。伐昔洛韦对降低VOC发生率的作用不显著，然而，其对提高血红蛋白水平的作用显著（p = <0.001）。在所有三种疗法中，疼痛是参与者报告的最常见不良事件。联合疗法分析显示，伐昔洛韦加L-谷氨酰胺具有协同作用，伐昔洛韦加克立唑单抗具有拮抗作用，L-谷氨酰胺加克立唑单抗具有相加作用。因此，伐昔洛韦加L-谷氨酰胺联合疗法可能对镰状细胞病患者更有益。因此，应启动针对SCD中使用的获批疗法的强有力的联合药物研究，特别关注伐昔洛韦加L-谷氨酰胺。此外，还应优先开发减轻镰状细胞病患者疼痛负担的药物。
