Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.
Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.
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DOI：
10.1001/jamaneurol.2013.5528
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发表时间：
2014-02
期刊：
影响因子：
29
通讯作者：
Eaton, Ken
中科院分区：
文献类型：
--
作者：
Schwarzschild, Michael A.;Ascherio, Alberto;Beal, M. Flint;Cudkowicz, Merit E.;Curhan, Gary C.;Hare, Joshua M.;Hooper, D. Craig;Kieburtz, Karl D.;Macklin, Eric A.;Oakes, David;Rudolph, Alice;Shoulson, Ira;Tennis, Marsha K.;Espay, Alberto J.;Gartner, Maureen;Hung, Albert;Bwala, Grace;Lenehan, Richard;Encarnacion, Elmyra;Ainslie, Melissa;Castillo, Richard;Togasaki, Daniel;Barles, Gina;Friedman, Joseph H.;Niles, Lisa;Carter, Julie H.;Murray, Megan;Goetz, Christopher G.;Jaglin, Jeana;Ahmed, Anwar;Russell, David S.;Cotto, Candace;Goudreau, John L.;Russell, Doozie;Parashos, Sotirios Andreas;Ede, Patricia;Saint-Hilaire, Marie H.;Thomas, Cathi-Ann;James, Raymond;Stacy, Mark A.;Johnson, Julia;Gauger, Lisa;de Marcaida, J. Antonelle;Thurlow, Sheila;Isaacson, Stuart H.;Carvajal, Lisbeth;Rao, Jayaraman;Cook, Maureen;Hope-Porche, Charlise;McClurg, Lauren;Grasso, Daniela L.;Logan, Robert;Orme, Constance;Ross, Tori;Brocht, Alicia F. D.;Constantinescu, Radu;Sharma, Saloni;Venuto, Charles;Weber, Joseph;Eaton, Ken
聚合的生物学，流行病学和临床数据确定尿酸盐升高作为减缓帕金森病（PD）残疾进展的候选策略。确定尿酸盐前体肌苷在早期PD中的安全性、耐受性和尿酸盐升高能力;并评估其适用性和疾病改善试验的潜在设计特征。PD中尿酸升高的安全性（SURE-PD）研究是一项随机、双盲、安慰剂对照、肌苷剂量范围试验，招募了2009-2011年的参与者，并对他们进行了长达25个月的随访。门诊访问美国帕金森研究组的17个有资质的临床研究中心。入组了75名同意的早期PD成人（平均年龄62岁; 55%为女性），这些患者尚不需要对症治疗，血清尿酸盐浓度低于6 mg/dL（近似人群中位数）。参与者被随机分配到三个治疗组之一：安慰剂或肌苷滴定，以产生轻度（6.1-7.0 mg/dL）或中度（7.1-8.0 mg/dL）血清尿酸盐升高，使用500 mg胶囊口服，每天最多两次。对他们进行了长达24个月（中位数18）的研究药物随访，加上1个洗脱月。预先规定的主要结局是没有不可接受的严重不良事件（安全性），继续治疗而没有需要降低剂量的不良事件（耐受性），以及血清中连续评估的尿酸盐升高和脑脊液（CSF）中的一次（3个月时）。严重不良事件（17），包括罕见的心血管事件，发生率在肌苷组与安慰剂组相同或更低。没有参与者发生痛风，三名接受肌苷治疗的患者出现症状性尿石症。95%的参与者在6个月时耐受治疗，没有参与者因不良事件退出。与安慰剂组相比，两个肌苷组的血清尿酸盐升高了2.3和3.0 mg/dL（p<0.001），两个肌苷组的CSF尿酸盐更高（分别为p=0.006和<0.001）。次要分析表明肌苷治疗对减缓残疾无效。肌苷通常是安全的，可耐受的，并有效地提高早期PD的血清和CSF尿酸水平。研究结果支持推进肌苷作为PD潜在疾病改善疗法的更明确发展。ClinicalTrials.gov NCT 00833690（http：//clinicaltrials.gov/ct2/show/NCT 00833690）
Convergent biological, epidemiological and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability and urate-elevating capability of the urate precursor inosine in early PD; and to assess its suitability and potential design features for a disease-modification trial. The Safety of URate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009–2011 and followed them for up to 25 months. Outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age 62; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration below 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to one of three treatment arms: placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation using 500 mg capsules taken orally up to two thrice daily. They were followed for up to 24 months (median 18) on study drug plus 1 washout month. The pre-specified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid (CSF). Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in inosine groups relative to placebo. No participant developed gout and three receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew due to an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the two inosine groups (p<0.001 for each) vs placebo, and CSF urate was greater in both inosine groups (p=0.006 and <0.001, respectively). Secondary analyses demonstrated non-futility of inosine treatment for slowing disability. Inosine was generally safe, tolerable, and effective in raising serum and CSF urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. ClinicalTrials.gov NCT00833690 (http://clinicaltrials.gov/ct2/show/NCT00833690)
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影响因子：
5.6
作者：
Soltani, Zohreh;Rasheed, Kashaf;Kapusta, Daniel R.;Reisin, Efrain
通讯作者：
Reisin, Efrain
DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
HOCHSTEIN, P
影响因子：
4.7
作者：
Gong, Li;Zhang, Qi-Lin;Luo, Wei-Feng
通讯作者：
Luo, Wei-Feng
影响因子：
--
作者：
Schwarzschild, Michael A.;Schwid, Steven R.;Ascherio, Alberto
通讯作者：
Ascherio, Alberto
影响因子：
9.8
作者：
Yamamoto, T;Moriwaki, Y;Hada, T
通讯作者：
Hada, T