Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.
Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.
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DOI：
10.3390/jcm9113682
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发表时间：
2020-11-16
影响因子：
3.9
通讯作者：
Drazinic C
中科院分区：
文献类型：
--
作者：
Brownstein MJ;Simon NG;Long JD;Yankey J;Maibach HT;Cudkowicz M;Coffey C;Conwit RA;Lungu C;Anderson KE;Hersch SM;Ecklund DJ;Damiano EM;Itzkowitz DE;Lu S;Chase MK;Shefner JM;McGarry A;Thornell B;Gladden C;Costigan M;O'Suilleabhain P;Marshall FJ;Chesire AM;Deritis P;Adams JL;Hedera P;Lowen K;Rosas HD;Hiller AL;Quinn J;Keith K;Duker AP;Gruenwald C;Molloy A;Jacob C;Factor S;Sperin E;Bega D;Brown ZR;Seeberger LC;Sung VW;Benge M;Kostyk SK;Daley AM;Perlman S;Suski V;Conlon P;Barrett MJ;Lowenhaupt S;Quigg M;Perlmutter JS;Wright BA;Most E;Schwartz GJ;Lamb J;Chuang RS;Singer C;Marder K;Moran JA;Singleton JR;Zorn M;Wall PV;Dubinsky RM;Gray C;Drazinic C
SRX246是一种抗利尿激素（AVP） 1a受体拮抗剂，可穿过血脑屏障。在动物模型中，它减少了冲动攻击、恐惧、抑郁和焦虑，在实验医学功能磁共振成像研究中，它阻断了鼻内AVP对攻击/恐惧回路的作用，并在1期多次上升剂量临床试验中显示出极好的安全性。本研究是一项3组、多中心、随机、安慰剂对照、双盲、12周、剂量递增的SRX246治疗伴有易怒症状的早期亨廷顿病（HD）患者的研究。我们的目标是确定SRX246在这些HD患者中是否安全且耐受性良好，因为它可能用于治疗有问题的神经精神症状。参与者随机接受安慰剂或升级至120 mg每日两次或160 mg每日两次的SRX246剂量。评估包括标准安全测试、统一亨廷顿氏病评定量表（UHDRS）和问题行为的探索性测量。两组在人口统计学、HD特征和基线易怒性方面具有可比性。106名受试者中有82人随机完成了他们指定剂量的药物试验。使用单侧精确方法置信区间检验来拒绝每个剂量组的耐受性或安全性低于安慰剂的原假设。SRX246对冷漠和自杀行为没有影响。活性组的大多数不良事件被认为不太可能与SRX246相关。该化合物在HD患者中是安全且耐受性良好的，可以作为治疗易怒和攻击的候选药物。
SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
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影响因子：
2.3
作者：
Fagerland, Morten W.;Lydersen, Stian;Laake, Petter
通讯作者：
Laake, Petter
DOI：
10.1016/0197-2456(82)90024-1
发表时间：
1982-01-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
BLACKWELDER, WC
通讯作者：
BLACKWELDER, WC
影响因子：
4.4
作者：
Nielsen, Signe Marie Borch;Vinther-Jensen, Tua;Josefsen, Knud
通讯作者：
Josefsen, Knud
DOI：
10.2174/157488908784534586
发表时间：
2008-06-01
期刊：
Recent patents on CNS drug discovery
影响因子：
--
作者：
Simon, Neal G;Guillon, Christophe;Koppel, Gary A
通讯作者：
Koppel, Gary A
DOI：
10.1007/978-3-319-71779-1_1
发表时间：
2018-01-01
期刊：
POLYGLUTAMINE DISORDERS
影响因子：
--
作者：
Ghosh, Rhia;Tabrizi, Sarah J.
通讯作者：
Tabrizi, Sarah J.