Sleep Research Institute, Madrid, Spain.
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Sleep Med. 2018 May;45:94-97. doi: 10.1016/j.sleep.2018.02.002. Epub 2018 Feb 24.
Recent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms.
In a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score).
Thirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing.
These preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS.
The study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.
最近的不宁腿综合征（RLS）动物模型表明，脑铁缺乏与低腺苷能状态有关，纹状体和皮质中的腺苷 A 受体（A1R）下调。我们假设，腺苷转运体抑制剂（如非选择性 ENT1/ENT2 抑制剂双嘧达莫）诱导细胞外腺苷增加，将导致 RLS 症状改善。
在一项为期两个月的前瞻性、非安慰剂对照临床试验中，15 名未经治疗的特发性 RLS 患者开始接受 100mg 双嘧达莫（必要时滴定至 400mg）治疗。在基线和 8 周时进行多项建议的固定测试和多导睡眠图检查。在第 4 周和第 8 周使用 IRLS 和 CGI 量表评估严重程度。主要终点是治疗反应（IRLS 总分改善 50%）。
13 名患者完成了研究。IRLS 评分从基线时的平均（±标准差）23.4±4.6 改善到 8 周时的 10.7±4.5。13 名患者中有 6 名是完全应答者，4 名是部分应答者。8 周时双嘧达莫的平均（±标准差）有效剂量为 281.8±57.5mg/天。睡眠变量也有所改善，平均（±标准差）周期性肢体运动指数从 26.7±7.2 降至 4.3±1.9。双嘧达莫通常耐受良好。主要副作用是腹痛、腹泻、头晕和脸红。
这些初步结果表明，双嘧达莫对感觉和运动症状以及睡眠均有显著的治疗作用。此外，它提供了证据表明低腺苷能机制在 RLS 中起核心作用。
该研究提供了 III 级证据，支持双嘧达莫治疗 RLS 的疗效。
