Novel Oral Nanoparticle Formulation of Sustained Release Naloxone with Mild Withdrawal Symptoms in Mice.,ACS Chemical Neuroscience

当前位置： X-MOL 学术 › ACS Chem. Neurosci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Novel Oral Nanoparticle Formulation of Sustained Release Naloxone with Mild Withdrawal Symptoms in Mice.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-06-03 , DOI: 10.1021/acschemneuro.0c00141
Caitlin A Madison ₁ , Meenakshi Arora ₂ , M N V Ravi Kumar ₂ , Shoshana Eitan ₁

Affiliation

Chronic use of opioids can lead to tolerance, dependence, abuse, and addiction. This in turn can result in dose escalation and opioid overdose. Opioid overdose can be fatal due to severe opioid-induced respiratory depression (OIRD). Naloxone, a nonspecific antagonist of the mu-opioid receptors, is used for the reversal of OIRD. However, one of the major challenges of using naloxone is its short elimination half-life, which is significantly shorter compared to many opioid analgesics. Thus, renarcotization and rapid return to full respiratory depression might occur, specifically in individuals who have taken large doses or long-acting opioid formulations. Additionally, because of the very low oral bioavailability of naloxone, an oral formulation is not currently available. This study examines in mice a novel oral formulation of naloxone based on polymer nanoparticles (NP-naloxone). A single dose of 1 or 5 mg/kg NP-naloxone was highly effective at inhibiting the activating effects of repeated administration of 10 mg/kg morphine for at least up to 24 h. Onset of action was approximately 5 min. Reversal of morphine-induced locomotion was already detected within 1 min and a full effect of returning to baseline activity levels was observed within 5 min. Importantly, at 1 mg/kg, NP-naloxone precipitated very minimal withdrawal behaviors. At the 5 mg/kg dose, NP-naloxone precipitated approximately 40% of the jumping withdrawal behaviors of injectable naloxone. Thus, this study demonstrates that orally administered naloxone based on polymer nanoparticles has high potential to be developed to circumvent OIRD and withdrawal symptoms.

中文翻译：

纳洛酮缓释症状小鼠的新型口服纳米颗粒制剂。

长期使用阿片类药物会导致耐受，依赖性，滥用和成瘾。这又可能导致剂量增加和阿片类药物过量。由于严重的阿片类药物引起的呼吸抑制（OIRD），阿片类药物过量可能致命。纳洛酮是一种μ阿片受体的非特异性拮抗剂，可用于OIRD的逆转。然而，使用纳洛酮的主要挑战之一是其消除半衰期短，与许多类阿片类镇痛药相比，其半衰期要短得多。因此，特别是在服用大剂量或长效阿片类药物的个体中，可能发生重新麻醉并迅速恢复为完全的呼吸抑制。另外，由于纳洛酮的口服生物利用度非常低，因此目前没有口服制剂。这项研究在小鼠中研究了一种基于聚合物纳米颗粒（NP-纳洛酮）的新型纳洛酮口服制剂。单剂1或5 mg / kg NP-纳洛酮对抑制重复给药10 mg / kg吗啡至少长达24小时的激活效果非常有效。作用开始约5分钟。在1分钟内已经检测到吗啡诱导的运动发生逆转，并且在5分钟内观察到完全恢复到基线活动水平的效果。重要的是，在1 mg / kg时，NP-纳洛酮沉淀出的戒断行为极少。在5 mg / kg剂量下，NP-纳洛酮沉淀了可注射纳洛酮跳跃性戒断行为的约40％。从而，

更新日期：2020-07-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11