己酮可可碱通过对血液透析患者缺氧诱导因子-2α的新作用改善贫血：一项随机、双盲、安慰剂对照临床试验。

Pentoxifylline improves anemia through its novel effect on hypoxia-inducible factor-2 alpha in hemodialysis patients: a randomized, double-blind, placebo-controlled clinical trial.

机构信息

Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.

Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

出版信息

Postgrad Med. 2024 Nov;136(8):847-854. doi: 10.1080/00325481.2024.2426448. Epub 2024 Nov 10.

DOI:10.1080/00325481.2024.2426448

PMID:39499142

Abstract

OBJECTIVES

This randomized, double-blind, placebo-controlled clinical trial aimed to prospectively examine the effect of pentoxifylline (PTX) on hypoxia-inducible factor-2 alpha (HIF-2α) and its role in controlling anemia in hemodialysis (HD) patients.

METHODS

Eighty patients on HD were randomized to receive 400 mg of PTX or placebo twice daily for 6 months. The hemoglobin (Hb) and other hematologic parameters, the weekly erythropoiesis-stimulating agents (ESAs), and the ESA resistance index (ERI) were assessed monthly during the study. The HIF-2α, transforming growth factor-β1 (TGF-β1), and high-sensitivity C-reactive protein (hs.CRP) were measured before and after the intervention.

RESULTS

In the pentoxifylline group, an appreciable increase in Hb from 9.7 (9.3, 10.3) g/dl to 10.5 (9.3, 11.4) g/dl and hematocrit (Hct) from 31.3 (29.6, 32.4)% to 33.2 (29.4, 35.9)% was observed after one month of PTX administration, and this effect was maintained over the study time ( < 0.001). This was along with a decrease in the ESA doses required from 8000 (8000, 11500) IU/wk to 4000 (2000, 8000) IU/wk ( < 0.001), and an improvement in the ERI from 11.6 (8.07, 16.97) IU/kg/wk/g/dl to 5.79 (2.01, 10.09) IU/kg/wk/g/dl ( < 0.001). Additionally, the HIF-2α increased significantly at the end of the intervention in patients who received PTX from 3245.35 (2886.8, 4691.56) pg/ml to 7208.75 (5382, 9182.7) pg/ml, while TGF-β1 and hs.CRP decreased significantly from 657.78 (539.78, 1146.62) pg/ml and 88.08 (39.93, 100.4) mg/l to 329.94 (228.67, 793.18) pg/ml and 48.65 (34.44, 84.61) mg/l, respectively. The percent changes in HIF-2α, TGF-β1, and hs.CRP levels in the pentoxifylline group were also statistically significant in comparison with the placebo group.

CONCLUSIONS

PTX could be a promising agent for correcting anemia in HD patients via increasing HIF-2α levels.

CLINICAL TRIAL REGISTRATION

Clinicaltrials.gov, February 2023, registry number: NCT05708248.

摘要

目的

本随机、双盲、安慰剂对照的临床试验旨在前瞻性研究己酮可可碱（PTX）对低氧诱导因子-2α（HIF-2α）的影响及其在控制血液透析（HD）患者贫血中的作用。

方法

80 名 HD 患者被随机分为两组，分别接受每天两次 400mg PTX 或安慰剂治疗 6 个月。在研究期间，每月评估血红蛋白（Hb）和其他血液学参数、每周促红细胞生成素刺激剂（ESAs）和 ESA 抵抗指数（ERI）。在干预前后测量 HIF-2α、转化生长因子-β1（TGF-β1）和高敏 C 反应蛋白（hs.CRP）。

结果

在 PTX 组中，Hb 从 9.7（9.3，10.3）g/dl 增加到 10.5（9.3，11.4）g/dl，Hct 从 31.3（29.6，32.4）%增加到 33.2（29.4，35.9）%，在 PTX 给药一个月后观察到明显的增加，并且这种效果在整个研究期间都保持着（ < 0.001）。这伴随着所需 ESA 剂量从 8000（8000，11500）IU/周减少到 4000（2000，8000）IU/周（ < 0.001），ERI 从 11.6（8.07，16.97）IU/kg/周/g/dl 改善到 5.79（2.01，10.09）IU/kg/周/g/dl（ < 0.001）。此外，接受 PTX 的患者的 HIF-2α 在干预结束时显著增加，从 3245.35（2886.8，4691.56）pg/ml 增加到 7208.75（5382，9182.7）pg/ml，而 TGF-β1 和 hs.CRP 则显著降低，从 657.78（539.78，1146.62）pg/ml 和 88.08（39.93，100.4）mg/l 分别降低到 329.94（228.67，793.18）pg/ml 和 48.65（34.44，84.61）mg/l。PTX 组 HIF-2α、TGF-β1 和 hs.CRP 水平的百分比变化与安慰剂组相比也具有统计学意义。