Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans
Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans
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DOI：
10.1007/s002130100788
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发表时间：
2001-09-01
影响因子：
3.4
通讯作者：
Bigelow, GE
中科院分区：
文献类型：
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作者：
Walsh, SL;Strain, EC;Bigelow, GE
理由：高选择性和特异性kappa阿片受体激动剂enadoline的可用性为探索人类kappa受体的功能及其作为药物滥用药物治疗发展目标的潜在效用提供了机会。目的：本研究的目的是表征选择性卡帕受体激动剂依纳多林的药效学作用，并将其与布托啡诺（一种混合的卡帕受体激动剂）和氢吗啡酮（一种受体激动剂）在人体中的作用进行比较。方法：初步评估（n=3）旨在建立肌内注射依纳多林（20、40、80和160马克/70公斤）、丁托啡诺（1.5、3、6和12毫克/70公斤）和氢吗啡酮（1.5、3和6毫克/70公斤）具有类似活性的剂量。这些急性剂量是在双盲、安慰剂对照和约束随机条件下进行的，在有多种药物滥用史的志愿者中，两次试验之间至少间隔72小时（n=6）。在给药前30分钟和给药后4小时收集生理指标和受试者及观察者评价指标。结果：依纳多林显著增加镇静、混乱和头晕，产生视觉扭曲和人格解体感，并增加尿量。最高剂量（160杯/70公斤）不能耐受并导致拟精神效应。氢吗啡酮产生典型的mu阿片效应，包括呼吸抑制、瞳孔缩小和欣快感。布托啡诺与氢吗啡酮最相似，与依纳多林作用不大。结论：这些结果讨论了kappa激动剂在临床适应症中的潜在应用和安全性。
Rationale: The availability of the highly selective and specific kappa opioid agonist enadoline provides an opportunity to explore the function of kappa receptors in humans and their potential utility as a target for substance abuse pharmacotherapy development. Objectives: The purpose of this study was to characterize the pharmacodynamic effects of enadoline, a selective kappa agonist, and to compare it with butorphanol, a mixed mu/kappa agonist, and hydromorphone, a mu agonist, in humans. Methods: Pilot evaluation (n=3) served to establish intramuscular doses of enadoline (20, 40, 80, and 160 mug/70 kg), butorphanol (1.5, 3, 6, and 12 mg/70 kg), and hydromorphone (1.5, 3, and 6 mg/70 kg) of comparable activity. These acute doses were examined under double-blind, placebo-controlled and constrained randomized conditions with a minimum of 72 h between tests in volunteers with polysubstance abuse histories (n=6). Physiological and subject- and observer-rated measures were collected 30 min before and for 4 h after administration. Results: Enadoline significantly increased measures of sedation, confusion and dizziness, produced visual distortions and feelings of depersonalization, and increased urinary output. The highest dose (160 mug/70 kg) was not tolerated and led to psychotomimetic effects. Hydromorphone produced prototypic mu opioid effects including respiratory depression, miosis, and euphoria. Butorphanol was most similar to hydromorphone and shared few effects with enadoline. Conclusions: These results are discussed with respect to the potential use and safety of kappa agonists for clinical indications.