Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence.
Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence.
复制标题
对有或没有可卡因依赖的人重复施用 Opra Kappa (LY2456302)，一种新型、短效、选择性 KOP-r 拮抗剂。
DOI：
10.1038/npp.2017.205
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Kreek,MaryJeanne
中科院分区：
文献类型：
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作者：
Reed,Brian;Butelman,EduardoR;Fry,RebeccaS;Kimani,Rachel;Kreek,MaryJeanne
κ-阿片受体 (KOP-r) 系统及其内源性配体强啡肽参与成瘾状态和情绪的神经生物学调节。关于人类选择性 KOP-r 拮抗剂对基本生物行为功能或成瘾性疾病和情绪障碍的影响的数据有限。先前研究的选择性 KOP-r 拮抗剂具有不寻常的药效学和药代动力学特性（KOP-r 选择性发展缓慢，作用持续时间极长），这限制了其在人类研究中的转化。最近开发的选择性 KOP-r 拮抗剂 Opra Kappa (LY2456302；CERC-501) 具有类似药物的作用持续时间、口服生物利用度和靶标参与度。目前的研究是首次调查 KOP-r 拮抗剂对可卡因依赖者与正常志愿者的影响。在压力最小化的住院患者环境中，我们确定了重复施用活性剂量的 Opra Kappa（每天 10 毫克口服，与初始基线日相比连续四天）对神经内分泌和神经行为的影响。研究对象包括健康志愿者 (n = 40)、早期戒断中被诊断为可卡因依赖的人 (< 2 个月，EACD) (n = 23) 和未吸毒的前可卡因依赖者 (戒断 7 个月至 25 年，DFFFD) (n = 7)，测量数据包括循环神经内分泌激素、情感，以及可卡因依赖者的可卡因渴望。与 Opra Kappa 相关的适度不良事件包括在一小部分个体中观察到的瘙痒症。 Opra Kappa 给药后，血清催乳素水平没有观察到显着变化，但观察到循环促肾上腺皮质激素和皮质醇适度增加。在这种压力最小化的环境中，抑郁症或可卡因渴望的测量结果没有显着变化。总体而言，这些研究表明 10 mg Opra Kappa 的效果与选择性 KOP-r 拮抗剂的预测效果基本一致。这种药物治疗方案是可以耐受的，因此可用于可卡因依赖者的进一步研究。
The κ-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg po daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n= 40), persons diagnosed with cocaine dependence in early abstinence (< 2 months, EACD)(n= 23), and drug-free former cocaine-dependent persons (7-month to 25-year abstinence, DFFCD)(n= 7) were studied, with measurements including circulating neuroendocrine hormones, affect, and, in cocaine-dependent persons, cocaine craving. Modest adverse events related to Opra Kappa included pruritus, observed in a subset of individuals. No significant change was observed in serum prolactin levels following Opra Kappa administration, but modest increases in circulating adrenocorticotropic hormone and cortisol were observed. No significant changes were noted in measures of depression or cocaine craving in this stress-minimized setting. Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist. This medication regimen was tolerable, and is therefore feasible for further studies in cocaine-dependent persons.