Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M(1) receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.
Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M(1) receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.
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DOI：
10.1186/s13195-021-00816-5
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发表时间：
2021-04-21
期刊：
影响因子：
--
通讯作者：
Nathan PJ
中科院分区：
文献类型：
--
作者：
Bakker C;Tasker T;Liptrot J;Hart EP;Klaassen ES;Doll RJ;Brown GA;Brown A;Congreve M;Weir M;Marshall FH;Cross DM;Groeneveld GJ;Nathan PJ
胆碱能系统和M1受体仍然是认知功能障碍对症治疗的重要靶点。选择性M1受体部分激动剂HTL 0018318正在开发中，用于对症治疗痴呆症，包括阿尔茨海默病（AD）和路易体痴呆症（DLB）。我们在健康的年轻成人和老年受试者中研究了HTL 0018318多次给药的安全性、耐受性、药代动力学和探索性药效学。进行了该随机、双盲、安慰剂对照研究，在7个健康年轻成人（n = 36; 3个队列）和老年（n = 50; 4个队列）受试者队列中研究了15-35 mg/天HTL 0018318或安慰剂的口服剂量。进行安全性、耐受性和药代动力学测量。使用一系列神经认知任务和突触和认知功能的电生理学生物标志物评估药效学。HTL 0018318在高达35 mg/天的多次给药中通常耐受良好，并与轻度或中度胆碱能不良事件相关。与安慰剂治疗受试者相比，血压和脉率适度升高，重复给药后血压升高趋势减弱。在ECG和24小时霍尔特评估中，血液和尿液实验室安全性指标或异常无临床显著观察结果或变化。在15-35 mg范围内，HTL 0018318血浆暴露量与剂量成比例。1-2 h后达到最大血浆浓度。稳态时，HTL 0018318的表观终末半衰期在年轻成人受试者中为16.1 h（± 4.61），在老年受试者中为14.3 h（± 2.78）。在10天的处理中，HTL 0018318对短期（工作）记忆（n-back）和学习（米尔纳迷宫）的测试具有显著影响，具有中等至大的效应量。HTL 0018138的多次给药显示出良好的药代动力学特征，并且在研究的剂量范围内是安全的，通常耐受良好。在整个剂量范围内均证明了对短期记忆和学习的促认知作用。这些数据提供了令人鼓舞的数据，支持开发HTL 0018138治疗AD和DLB中的认知功能障碍。荷兰试验注册标识符NTR 5781。于2016年3月22日注册。在线版本包含补充材料，可通过10.1186/s13195-021-00816-5获得。
The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia’s including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15–35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15–35 mg. Maximum plasma concentrations were achieved after 1–2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Netherlands Trial Register identifier NTR5781. Registered on 22 March 2016. The online version contains supplementary material available at 10.1186/s13195-021-00816-5.
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DOI：
10.1124/jpet.115.226712
发表时间：
2015-12-01
影响因子：
3.5
作者：
Lange, Henry S.;Cannon, Christopher E.;Uslaner, Jason M.
通讯作者：
Uslaner, Jason M.
影响因子：
11
作者：
Rombouts, SARB;Barkhof, F;Scheltens, P
通讯作者：
Scheltens, P
DOI：
10.1124/jpet.301.1.129
发表时间：
2002-04-01
影响因子：
3.5
作者：
Hardouin, SN;Richmond, KN;Nathanson, NM
通讯作者：
Nathanson, NM
DOI：
10.1093/cercor/bhv227
发表时间：
2016-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
通讯作者：
Mellor JR
影响因子：
--
作者：
Bodick, NC;Offen, WW;Paul, SM
通讯作者：
Paul, SM