High-dose allopurinol, a safe and inexpensive xanthine oxidase inhibitor used for decades for the treatment of gout, also appears to be an effective anti-ischemic drug in patients with angina pectoris, according to findings from a randomized, placebo-controlled study.

In 65 patients in the double-blind crossover study, allopurinol was shown during a standard exercise test to significantly improve median overall time to ST depression – the primary end point of the study – by a point estimate (the absolute difference between allopurinol and placebo) of 43 seconds, for a 19% improvement. It also significantly improved median exercise time and time to chest pain by point estimates of 58 and 38 seconds, respectively, Dr. Awsan Noman of the University of Dundee, Scotland, and colleagues reported online June 8 in The Lancet.

Time to ST depression improved from 232 seconds at baseline to 249 seconds and 298 seconds in the placebo and treatment groups, respectively; total exercise time improved from 301 seconds at baseline to 307 seconds and 393 seconds in the two groups, respectively; and time to symptoms improved from 234 seconds at baseline to 272 seconds and 304 seconds in the two groups, respectively, the investigators reported (Lancet 2010 June 8 [doi:10.1016/S0140-6736(10)60391-1]).

The patients were aged 18-85 years and had angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris for at least 2 months prior to enrollment. They were randomized to receive allopurinol daily or placebo for 6 weeks. Allopurinol in the first phase of the study was given at a dose of 100 mg once daily in the first week, 300 mg once daily in the second week, and 300 mg twice daily in weeks 3-6; the 600-mg daily dose was used in the crossover phase, which immediately followed the first phase, because it was shown to be the most effective dose for improving endothelial function and oxidative stress, they said.

The findings suggest that “endogenous xanthine oxidase activity contributes somehow to exercise-induced myocardial ischaemia,” the investigators wrote, adding that the magnitude of the anti-ischemic effect of allopurinol in this study appeared similar to that seen with other antianginal drugs. For example, reported improvements with amlodipine, nitrates, phosphodiesterase inhibitors, ivabradine, and atenolol and ranolazine in prior studies were 13%, 11%, 14%, 13.5%, and 15%, vs. placebo, respectively, they reported.

“Allopurinol might now be regarded as a potential drug for angina,” the investigators wrote, citing numerous advantages over other available antianginal drugs, including lower cost, a favorable long-term safety record over more than 40 years of use in gout patients, and better tolerability; allopurinol does not reduce blood pressure or heart rate, and does not cause side effects such as headache and tiredness common with nitrates and beta-blockers, they noted.

Further study is needed to better characterize the “the precise place of allopurinol in the management of angina pectoris,” but it may be a particularly appealing drug for use in developing countries where the availability of more expensive treatments is limited, they concluded.

Stable angina is the most frequent initial presentation of coronary heart disease; it can lead to acute coronary syndrome, particularly in higher risk groups; and it has high rates of residual symptoms and impaired quality of life even in well managed patients. Nonetheless, the condition has received little attention, compared with unstable angina and other acute coronary syndromes, Dr. Renjith Antony and Dr. Henry J. Dargie, of the Scottish Advanced Heart Failure Service, Golden Jubilee National Hospital, West Dunbartonshire, Scotland, said in an editorial.

The report by Dr. Noman and colleagues is interesting and welcome in that it will “focus attention on the unmet needs of patients with the most common, and frequently troublesome, manifestation of coronary heart disease,” they wrote (Lancet 2010 June 8 [doi:10.1016/S0140-6736(10)60578-8]).

“Xanthine oxidase inhibition by allopurinol is yet another non-haemodynamic action that could be exerting its putative anti-ischaemic effects by various mechanisms,” they said, comparing allopurinol with nicorandil, ranolazine, and other drugs that have antianginal effects ascribed to non-hemodynamic effects.

Although more work is needed to confirm allopurinol’s effects and better understand its mechanism of action, it appears to be one of a number of compounds that challenge the concept of what constitutes antianginal therapy, they said.

“Although prevention of coronary artery disease remains important, protecting the myocyte from ischaemia is a logical and pragmatic approach to a disabling condition for which several mechanisms might be responsible,” they added.

The University of Dundee and one of the study authors have applied for a patent for the use of xanthine oxidase inhibitors to treat anginal chest pain. Dr. Noman and the other authors declare that they have no conflicts of interest. Dr. Antony and Dr. Dargie indicated that they have no financial conflicts.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

别嘌呤醇是一种安全而廉价的黄嘌呤氧化酶抑制剂类药物，数十年来一直被用于痛风治疗。据一项随机、安慰剂对照的研究结果，高剂量的别嘌呤醇对心绞痛患者而言似乎还是一种有效的抗缺血药物。

 

据苏格兰Dundee大学的Awsan Noman博士及其同事6月8日在线发表于《柳叶刀》(The Lancet)上的一篇论文，在这项纳入65例患者的双盲交叉研究中，据一项标准运动试验的结果显示，别嘌呤醇可显著延长患者发生ST段压低(该研究的主要终点)的总体中位时间——对该数值进行点估计(别嘌呤醇和安慰剂之间的绝对差异)的结果为43s，该时间延长了19%。该药物还显著延长了患者运动和胸痛发作的中位时间，其点估计结果分别为58s和38s。

 

安慰剂组和治疗组的患者发生ST段压低的时间分别由基线值232s延长至249s和298s，两组患者的总运动时间分别由基线值301s延长至307s和393s，患者的基线值为234s，两组患者的症状发作时间分别由基线值234s延长至272s和304s，研究者们报告说(Lancet 2010 June 8 [doi:10.1016/S0140-6736(10)60391-1])。

 

患者的年龄介于18~85岁之间，且均患有经血管造影证实的冠状动脉疾病，其运动负荷试验结果呈阳性，且在加入研究前存在至少2个月以上的慢性稳定型心绞痛病史。这些患者被随机分配每日服用别嘌呤醇或安慰剂，治疗共持续6周。在该研究的第一阶段，患者在第1周每天服用一次别嘌呤醇，用药剂量为100mg，在第2周每天服药一次，剂量为300mg，在第3~6周每天服药2次，每次300mg，在紧接该研究第一阶段的交叉研究阶段中，患者每天的用药剂量为600mg，因为研究显示该剂量是用于改善血管内皮功能及缓解氧化应激压力的最有效剂量，他们说。

 

该研究结果显示“在某种程度上，内源性黄嘌呤氧化酶活性在运动诱导的心肌缺血病程中发挥了作用，”研究者们写道，其还补充说，该研究中别嘌呤醇所表现出的抗缺血效应的大小与既往观察到的其他抗心绞痛药物的效应类似。例如，既往研究所报道的由氨氯地平、硝酸酯类药物、磷酸二酯酶抑制剂、伊伐布雷定和阿替洛尔及雷诺嗪等药物所带来的改善效应与安慰剂相比分别为13%、11%、14%、13.5%和15%，他们报告说。

 

 “别嘌呤醇现在可能已被视为治疗心绞痛的潜在药物，”研究者们写道，与现有的其他抗心绞痛药物相比，该药存在众多优点，包括成本低廉、具备超过40年的用于痛风患者的良好长期安全记录，且患者对该药的耐受性较佳；别嘌呤醇不会降低患者的血压或心率，也不会导致头痛或疲劳之类的副作用，而这在患者应用硝酸酯类药物和β-受体阻断剂时则很常见，他们指出。

 

为了更好地描述“别嘌呤醇在心绞痛治疗中的确切作用”，还需要进行进一步的研究，但其对发展中国家而言是一种特别有吸引力的药物，因为在这些国家中应用更昂贵治疗药物受到了限制，他们总结说。

 

稳定型心绞痛是冠状动脉疾病最常见的早期表现，它可以引发急性冠脉综合征，尤其是对高危群体而言，且由该病所导致的残留症状和生活质量下降即便是在治疗状况良好的患者中也有很高的发生率。尽管如此，与不稳定型心绞痛和其他急性冠脉综合征相比，该病极少受到关注，苏格兰西丹巴顿郡金禧国家医院和苏格兰晚期心力衰竭服务系统(the Scottish Advanced Heart Failure Service)的Renjith Antony博士和Henry J. Dargie博士在编者按中说。

 

Noman博士及其同事的研究报告的有趣及受欢迎之处在于其将“集中关注那些伴有冠状动脉疾病最常见的、且常常是令人烦恼的症状的患者的未被满足的需求，”他们写道(Lancet 2010 June 8 [doi:10.1016/S0140-6736(10)60578-8])。

 

 “由别嘌呤醇对黄嘌呤氧化酶的抑制效应还是一种非血流动力学效应，该效应可以通过多种机制发挥其潜在抗缺血作用，”他们说，当他们比较别嘌呤醇和尼可地尔、雷诺嗪及抗心绞痛效应归因于非血流动力学机制的其他药物时。

 

尽管为了确认别嘌呤醇的疗效并更好地理解该药的作用机制还需要开展更多的工作，但该药似乎已经成为对抗心绞痛治疗模式构成挑战的众多化合物之一，他们说。

 

 “尽管预防冠状动脉疾病依旧重要，在预防可能由数种机制所导致的患者伤残时，预防心肌细胞缺血才是合乎逻辑的务实做法，”他们补充说。

 

Dundee大学和该研究的某位作者已就黄嘌呤氧化酶抑制剂用于治疗心绞痛胸痛申请了一项专利。Noman博士及其他作者宣称他们无利益冲突。Antony博士和Dargie博士表示他们不存在经济利害关系。

 

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