背景：在先前的研究中，M1/M4偏好毒蕈碱受体激动剂xanomeline证明了阿尔茨海默病或精神分裂症患者的抗精神病药和促认知作用，但进一步的临床发展受到胆碱能不良事件(AE)的限制.KarXT将xanomeline与外周限制性毒蕈碱受体拮抗剂trosspium联合使用，目的是提高耐受性，并且正在精神分裂症和其他神经精神疾病的临床开发中。
目的：检验曲司铵可以减轻与黄嘌呤相关的胆碱能AE的假设。
方法：健康志愿者参加此阶段1（NCT02831231），单站点,9天,单用xanomeline(n=33)与KarXT(n=35)的双盲比较。五种预设胆碱能AE的发生率(恶心，呕吐,腹泻,出汗过多,唾液分泌过多）在治疗组之间进行比较。生命体征,心电图(ECG),安全实验室值，和药代动力学（PK）分析进行评估。采用自我管理的视觉模拟量表（VAS）和临床医生管理的量表。
结果：与单独的xanomeline相比，KarXT将五种先验胆碱能AE的复合发生率降低了46％，每个单独的AE降低了≥29％。在KarXT治疗的受试者中没有晕厥发作；仅在xanomeline臂中发生了2例。KarXT臂的姿势性头晕率为11.4％，而仅xanomeline为27.2％。心电图,生命体征,和实验室值在治疗组之间没有显著差异.VAS和临床医生管理的量表倾向于支持KarXT。PK分析显示，曲司汀不影响xanomeline的PK谱。
结论：Trospium可有效缓解黄霉素相关的胆碱能AE。与单独使用xanomeline相比，KarXT具有改善的安全性。
BACKGROUND: The M1/M4 preferring muscarinic receptor agonist
xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer\'s disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines
xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders.
OBJECTIVE: Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.
METHODS: Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed.
RESULTS: Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with
xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect
xanomeline\'s PK profile.
CONCLUSIONS: Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with
xanomeline alone.
