国际帕金森研究小组SURE-PD3研究者Marie Saint-Hilaire团队探讨了肌苷升高尿酸对早期帕金森病进展的影响。这一研究成果发表在2021年9月14日出版的《美国医学会杂志》上。

尽管尿酸盐升高与晶体病变、心血管疾病和代谢紊乱有关，但基于汇聚了生物学、流行病学和临床学的数据，尿酸盐升高已被作为一种潜在的帕金森病（PD）缓解策略。

为了确定用尿酸盐前体肌苷持续提高尿酸盐治疗是否能延缓早期PD进展，研究组进行了一项口服肌苷治疗早期PD的随机、双盲、安慰剂对照、临床3期试验。2016年8月至2017年12月，研究组在美国58个地点共招募了587名患者，其中298名PD患者尚未需要多巴胺能药物治疗，纹状体多巴胺转运体缺乏，血清尿酸盐低于人群中位浓度（5.8 mg/dL），并随访至2019年6月。

将这298名患者随机分组，其中149例接受肌苷盲滴定给药，将血清尿酸盐浓度增加至7.1-8.0 mg/dL，另外149例接受匹配的安慰剂治疗，最多为期2年。主要结局是在开始多巴胺能药物治疗之前，运动障碍协会统一帕金森病评定量表（MDS-UPDRS）总分（范围0-236；分数越高表示残疾越严重；最小临床重要差异6.3分）的变化率。次要结局包括血清尿酸测定目标参与度，不良事件测定安全性，以及29项残疾、生活质量、认知、情绪、自主功能和作为神经元完整性生物标志物的纹状体多巴胺转运体结合疗效评估。

基于预先指定的中期无效性分析，研究提前结束，共有273名（92%）参与者（49%为女性；平均年龄63岁）完成了研究。肌苷组的MDS-UPDRS评分为11.1分，安慰剂组为9.9分，两组间临床进展率无显著差异。肌苷组的血清尿酸盐持续升高2.03 mg/dL，比基线增加了44%，而安慰剂组的血清尿酸盐仅升高0.01 mg/dL，两组间差异显著。两组间的次要疗效结局（包括多巴胺转运体结合丧失）无显著差异。与安慰剂组相比，肌苷组发生的严重不良事件较少（分别为每100患者-年7.4次和13.1次），但肾结石较多（每100患者-年7.0次和1.4次）。

研究结果表明，在新诊断为帕金森病的患者中，肌苷治疗与安慰剂治疗相比，在临床疾病进展率方面没有显著差异。研究结果不支持使用肌苷作为早期PD的治疗方法。

附：英文原文

Title: Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial

Author: The Parkinson Study Group SURE-PD Investigators, Brent Bluett, Daniel M. Togasaki, Dragos Mihaila, Marian Evatt, Michael Rezak, Samay Jain, Michael A. Schwarzschild, Alberto Ascherio, Cindy Casaceli, Gary C. Curhan, Rebecca Fitzgerald, Cornelia Kamp, Codrin Lungu, Eric A. Macklin, Kenneth Marek, Dariush Mozaffarian, David Oakes, Alice Rudolph, Ira Shoulson, Aleksandar Videnovic, Burton Scott, Lisa Gauger, Jason Aldred, Melissa Bixby, Jill Ciccarello, Steven A. Gunzler, Claire Henchcliffe, Matthew Brodsky, Kellie Keith, Robert A. Hauser, Christopher Goetz, Mark S. LeDoux, Vanessa Hinson, Rajeev Kumar, Alberto J. Espay, Joohi Jimenez-Shahed, Christine Hunter, Chadwick Christine, Aaron Daley, Maureen Leehey, J. Antonelle de Marcaida, Joseph Harold Friedman, Albert Hung, Grace Bwala, Irene Litvan, David K. Simon, Tanya Simuni, Cynthia Poon, Mya C. Schiess, Kelvin Chou, Ariane Park, Danish Bhatti, Carolyn Peterson, Susan R. Criswell, Liana Rosenthal, Jennifer Durphy, Holly A. Shill, Shyamal H. Mehta, Anwar Ahmed, Andres F. Deik, John Y. Fang, Natividad Stover, Lin Zhang, Richard B. Dewey, Ashley Gerald, James T. Boyd, Emily Houston, Valerie Suski, Sherri Mosovsky, Leslie Cloud, Binit B. Shah, Marie Saint-Hilaire

Issue&Volume: 2021/09/14

Abstract:

Importance  Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.

Objective  To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.

Design, Participants, and Setting  Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions  Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n=149) or matching placebo (n=149) for up to 2 years.

Main Outcomes and Measures  The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results  Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, 0.59 to 3.11] points per year; P=.18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions and Relevance  Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

DOI: 10.1001/jama.2021.10207

Source: https://jamanetwork.com/journals/jama/article-abstract/2784144