Adverse cardiovascular effects of allopurinol are related to the use of high doses.
Adverse cardiovascular effects of allopurinol are related to the use of high doses.
复制标题
别嘌呤醇的不良心血管作用与高剂量的使用有关。
DOI：
10.1097/hjh.0000000000002218
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发表时间：
2020
影响因子：
4.9
通讯作者：
M. Bredemeier
中科院分区：
文献类型：
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作者：
M. Bredemeier
我们祝贺作者进行了一项随机对照试验（RCT），帮助阐明了这样一个有争议的问题。作者观察到别嘌呤醇对心血管的有害影响可能与大多数患者是正常尿酸血症的事实有关，因此具有抗氧化特性的尿酸水平的降低可能会产生有害影响。虽然这是一个合理的解释，但可能还有其他可能的原因导致本研究中观察到的结果。两项针对心力衰竭的研究，OPT-CHF[2]和EXACT-HF[3]，分别测试了高剂量（600 mg/天）的氧嘌呤醇（别嘌呤醇的活性代谢物）和别嘌呤醇与安慰剂的比较。尽管OPT-CHF结果提示氧尿醇可能有害，但作者在亚组分析中观察到对高尿酸血症（9.5 mg/dl）患者有潜在的有益作用。与基线（11.4 mg/dl）相比，该亚组的尿酸水平降低了约30%。因此，为了希望别嘌呤醇能更好地治疗高尿酸血症患者，我们进行了EXACT-HF[3]研究，只包括尿酸至少为9.5 mg/dl的患者。别嘌呤醇组的平均尿酸水平（基线时11.0 mg/dl）降低了38.5%。然而，结果再次令人失望：别嘌呤醇组改善心力衰竭的患者数量在数字上较低（13%与安慰剂组的19%）。考虑到这两项研究的结果，大剂量别嘌呤醇在心力衰竭中的应用前景并不乐观。值得提醒的是，在这两项研究中，呋塞米的使用率约为90%，可显著提高血清氧尿醇[4]水平。除了Gingles等人的研究外，最近还有两项随机对照试验测试了大剂量别嘌呤醇对血管功能的影响。Borgi等人在平均尿酸为6.1 mg/dl的非高血压肥胖或超重个体中比较了大剂量别嘌呤醇（大多数患者接受600 mg/d）和安慰剂。别嘌呤醇组血清尿酸水平降低50%，但内皮依赖性血管舒张（EDV）和内皮非依赖性血管舒张（EIV）与安慰剂相比有数值上的恶化。Apex试验[6]是一项在心脏综合征X患者（平均尿酸5.4 mg/dl）中使用别嘌呤醇600 mg和安慰剂的交叉随机对照试验。在6周结束时，别嘌呤醇使血清尿酸降低了48%，但与安慰剂相比，EDV和EIV没有改善。这些结果与Gingles et al.[1]报道的结果相似，该研究包括控制高血压和左心室肥厚的患者。超过12个月，600 mg/天的别嘌呤醇不能改善EDV，显著增加TBARS（硫巴比妥酸反应物质，氧化应激标志物）水平，并损害左心室肥厚的消退。目前认为，别嘌呤醇的潜在心血管益处在于其通过抑制内皮结合的黄嘌呤氧化酶的抗氧化作用和/或其降血脂作用[7,8]，尽管后一种机制的证据正在逐渐消失[7,9]。在抗氧化作用方面，有证据表明，对黄嘌呤氧化酶活性的最大抑制作用发生在低浓度的氧嘌呤醇（40 mmol/l）[10,11]。Stamp等人（[4]）观察到，在服用别嘌呤醇平均剂量220 mg/天的个体中，氧嘌呤醇的平均浓度为88 mmol/l。因此，临床实践中通常使用的剂量远远高于产生内皮黄嘌呤氧化酶活性显著阻断所需的剂量。因此，低剂量的别嘌呤醇（<200毫克/天）通常应该足以获得所需的抗氧化效果。另一方面，与低剂量相比，使用高剂量别嘌呤醇可能与严重不良事件发生率增加有关。在最近的一项荟萃分析中，剂量大于300毫克与没有心血管益处有关，而较低剂量则显示出保护作用。一旦达到治疗效果的平台期，更高的剂量只会增加不良事件的强度和频率。较高浓度的氧嘌呤醇（100-150 mmol/l）可能与较高的氧化应激有关。高浓度的氧尿醇本身可以作为中性粒细胞释放的髓过氧化物酶的底物，产生一种能够将尿酸氧化为尿囊素[13]的自由基，并产生有害作用。此外，有证据表明，至少在易感个体中，剂量依赖性免疫系统激活与氧嘌呤醇[14]浓度增加有关。越来越多的证据表明，免疫系统的激活（包括超敏反应）在动脉粥样硬化的发病机制中起着重要作用[15,16]。在EXACT-HF研究中，高达10%的使用别嘌呤醇的患者出现了类似过敏的皮肤反应。金格尔斯和科尔斯的这项研究，以及其他最近发表的文章，进一步证明了大剂量别嘌呤醇实际上会对心血管造成有害影响。目前迫切需要比较不同别嘌呤醇剂量方案（包括200mg/天的剂量）的心血管效应和氧化应激标志物的随机对照试验。
W e congratulate the authors for conducing a randomized controlled trial (RCT) [1] that helps to shed light into such a controversial question. The authors observed that the deleterious cardiovascular effects of allopurinol may be related to the fact that most patients were normouricemic, and so the reduction in uric acid level, which has antioxidant properties, could have detrimental effects. Although this a reasonable explanation, there may be other possible causes to the results observed in this study. Two studies in heart failure, the OPT-CHF [2] and the EXACT-HF [3], tested oxypurinol (active metabolite of allopurinol) and allopurinol, respectively, at high doses (600 mg/day) in comparison with placebo. Despite the results of the OPT-CHF suggesting possible harm with oxypurinol, the authors observed in subgroup analysis a potential beneficial effect in patients with hyperuricemia ( 9.5 mg/dl). This subgroup presented a reduction in uric acid of approximately 30% in relation to baseline (which was 11.4 mg/dl) [2]. So, with the hope that allopurinol could do better in hyperuricemic patients, the EXACT-HF [3] study was performed including exclusively patients with uric acid at least 9.5 mg/dl. Mean uric acid level (11.0 mg/dl at baseline) reduced 38.5% in the allopurinol arm. However, the results were once again disappointing: the number of patients with improved heart failure was numerically lower with allopurinol (13 versus 19% in placebo). Considering the results of both studies, the prospects for the use of highdose allopurinol in heart failure are not good. It may be worth reminding that in both studies the prevalence of use of furosemide, which increases significantly the serum levels of oxypurinol [4], was about 90%. In addition to the study by Gingles et al. [1], two recent RCTs tested the effect of high-dose allopurinol on vascular function. Borgi et al. [5] compared high-dose allopurinol (most patients received 600 mg/day) and placebo in nonhypertensive obese or overweight individuals with mean uric acid of 6.1 mg/dl. There was a 50% reduction in serum uric acid level in allopurinol group, but there was a numerical worsening in endothelial-dependent (EDV) and endothelial-independent vasodilation (EIV) comparing with placebo. The Apex trial [6] was a cross-over RCT of allopurinol 600 mg and placebo in patients with cardiac syndrome X (mean uric acid, 5.4 mg/dl). At the end of 6 weeks, allopurinol reduced serum uric acid by 48% but failed to improve EDV and EIV in relation to placebo. These results are similar to those reported by Gingles et al. [1], which included patients with controlled hypertension and left ventricular hypertrophy. Over 12 months, allopurinol 600 mg/day failed to improve EDV, significantly increased the levels of TBARS (thiobarbituric acid reactive substances, markers of oxidative stress) and impaired the regression of left ventricular hypertrophy. It is currently believed that the potential cardiovascular benefits of allopurinol lie in its antioxidant effect by inhibiting endothelium-bound xanthine oxidase and/or in its hypouricemiant effect [7,8], despite the fact that evidence for the latter mechanism is fading [7,9]. Focusing on the antioxidant effect, there is evidence that almost maximum attainable inhibitory effect on xanthine oxidase activity occurs at low concentrations of oxypurinol (40 mmol/l) [10,11]. Stamp et al. [4] observed that the mean concentration of oxypurinol in individuals taking an average dose of allopurinol of 220 mg/day was 88 mmol/l. So, doses generally used in clinical practice are much higher than those necessary to produce a significant blockade of endothelial xanthine oxidase activity. Therefore, low doses of allopurinol (<200 mg/day) should be generally enough for obtaining the desired antioxidant effect. On the other hand, the use of high-dose allopurinol may be related to an increased incidence of serious adverse events in comparison to lower doses [12]. In a recent metaanalysis, doses greater than 300 mg were related to absence of cardiovascular benefits, whereas lower doses showed a protective effect [12]. Once the plateau of a therapeutic effect is reached, higher doses can only increase the intensity and frequency of adverse events. Higher concentrations of oxypurinol (>100–150 mmol/l) may be associated with higher oxidative stress. Oxypurinol at high concentrations can itself be a substrate for myeloperoxidase released by neutrophils, generating a radical capable of oxidizing uric acid to allantoin [13] and produce deleterious effects. Furthermore, there is evidence, at least in predisposed individuals, of a dose-dependent immune system activation associated with increasing concentrations of oxypurinol [14]. There is growing evidence that activation of the immune system (including hypersensitivity reactions) plays an important role in the pathogenesis of atherosclerosis [15,16]. In the EXACT-HF study [3], as much as 10% of the patients on allopurinol developed allergic-like skin reactions. The study by Gingles and colls [1], along with other recent publications, adds to the evidence that high-dose allopurinol can actually cause deleterious cardiovascular effects. RCTs comparing the cardiovascular effects and oxidative stress markers between different allopurinol dose regimens (including doses 200mg/day) are urgently needed.
DOI：
10.1007/s00018-015-1971-6
发表时间：
2015-10
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Wolf D;Zirlik A;Ley K
通讯作者：
Ley K