Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia.
Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia.
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α-7 烟碱受体正变构调节剂的初步交叉测试有助于患有或不患有精神分裂症的吸烟者戒烟。
DOI：
10.1038/npp.2017.292
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Brunzell,DarleneH
中科院分区：
文献类型：
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作者：
Perkins,KennethA;RoyChengappa,KN;Karelitz,JoshuaL;Boldry,MargaretC;Michael,Valerie;Herb,Taylor;Gannon,Jessica;Brar,Jaspreet;Ford,Lisa;Rassnick,Stefanie;Brunzell,DarleneH
临床前研究表明，作用于α7烟碱受体（nAChR）的化合物可减少尼古丁自我给药，表明α7受体的正变构调节剂（PAM）JNJ-39393406可能有助于戒烟。此外，吸烟率非常高的精神分裂症患者的α7 nAChR表达减少，可能特别受益于这种化合物。在两项采用受试者内交叉设计的平行研究中，36名健康吸烟者（研究1）和62名精神分裂症吸烟者（研究2），两组戒烟兴趣都很高，试图在两个3周阶段的每一个阶段暂时开始戒烟。治疗为α7烟碱受体PAM JNJ-39393406（100 mg bid）或安慰剂（双盲、反向平衡）。在每个阶段，所有人在第1周或第2周剂量启动期间无药物自由吸烟，然后在第3周每天尝试戒烟。戒烟（通过CO< 5 ppm证实）和吸烟减少（CO< 8），以及香烟/天（在研究1中），在每个戒烟周每天（周一至周五）进行评估，并在条件之间进行比较。次要结局包括戒断症状（戒断和渴望）和认知测试反应（N-back;连续性能任务）。在两项研究中，与安慰剂相比，活性JNJ-39393406未增加戒烟天数，也未减少总吸烟暴露量。我们还发现，在渴望、戒断或认知功能方面没有显著改善。在此剂量和研究持续时间下，我们的研究结果不支持进一步测试这种α7 nAChR PAM化合物在有或无精神分裂症的吸烟者中戒烟的可能疗效。
Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg bid) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO< 5 ppm) and smoking reduction (CO< 8), as well as cigarettes/day (in Study 1), were assessed daily (Monday–Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.