Joharapurkar Amit A, Patel Vishal J, Kshirsagar Samadhan G, Patel Maulik S, Savsani Hardikkumar H, Kajavadara Chetan, Valani Darshan, Jain Mukul R
Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad, Gujarat, India.
Curr Res Pharmacol Drug Discov. 2022 Apr 30;3:100102. doi: 10.1016/j.crphar.2022.100102. eCollection 2022.
Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 mg/kg, IP, single dose) and turpentine oil (5 mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 μg/kg) and desidustat (15 or 30 mg/kg) for eight weeks. Separately, rhEPO (1-5 μg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 μg/kg) for two weeks and then desidustat (15 mg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1β, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.
许多贫血的慢性肾脏病（CKD）患者由于炎症、铁利用紊乱和促红细胞生成素（EPO）抗体的产生而对EPO治疗无效。这项研究评估了低氧诱导因子（HIF）脯氨酰羟化酶（PHD）抑制剂地西司他对EPO抵抗性肾性贫血的影响。通过腹腔注射顺铂（5mg/kg，单次剂量）和皮下注射松节油（5mL/kg，每周一次）使Sprague Dawley大鼠贫血。这些大鼠接受重组人EPO（rhEPO，1μg/kg）和地西司他（15或30mg/kg）治疗八周。另外，给贫血大鼠注射rhEPO（1 - 5μg/kg）以维持正常血红蛋白水平，并给予地西司他（15mg/kg）八周。在另一项实验中，贫血大鼠先接受rhEPO（5μg/kg）治疗两周，然后接受地西司他（15mg/kg）治疗接下来的两周。rhEPO每周给药三次，地西司他隔天给药。地西司他抑制了rhEPO治疗引起的EPO抵抗，降低了铁调素、白细胞介素-6、白细胞介素-1β水平，并增加了铁和肝脏铁转运蛋白水平。地西司他减少了对EPO的需求和抗EPO抗体。在停止rhEPO治疗后，地西司他还能维持正常的血红蛋白水平。因此，新型脯氨酰羟化酶抑制剂地西司他可通过改善铁利用和减轻炎症来治疗EPO抵抗。
