Vivitrex®, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats
Vivitrex®, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats
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DOI：
10.1038/sj.npp.1300274
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发表时间：
2003-11-01
影响因子：
7.6
通讯作者：
Basile, AS
中科院分区：
文献类型：
--
作者：
Bartus, RT;Emerich, DF;Basile, AS
虽然口服纳洛酮可有效治疗酒精和阿片类药物依赖，但患者依从性差和血浆水平波动大限制了其疗效。为了克服这些问题，通过将纳洛酮包封到可注射的、可生物降解的聚合物微球中，开发了纳洛酮（Vivitrex（R））的延长释放制剂。大鼠药代动力学研究表明，该制剂在皮下或肌内注射后约1个月内产生稳定的、与药物相关的纳洛酮血浆水平。虽然接受安慰剂微球的大鼠在热板试验中对吗啡表现出明显的镇痛反应，但在用缓释纳洛酮治疗的大鼠中吗啡镇痛完全被阻断。这种拮抗作用从给药后第1天开始，持续28天。在初始剂量后34天重新注射缓释纳洛酮并测试另外35天的大鼠显示出持续抑制吗啡镇痛另外28天。通过[H-3] DAMGO放射自显影术测量的μ-阿片受体密度在单次注射缓释纳洛酮后增加高达两倍。使用[H-3] DAMGO的饱和结合试验显示，在缓释纳洛酮给药后1周，中脑和纹状体发生变化，1个月后，新皮质发生变化。这些受体的增加持续2-4周后，纳洛酮的吗啡拮抗剂作用消散。这些数据表明，纳洛酮的治疗相关血浆水平可以使用每月注射的缓释微球制剂来维持，并且μ阿片受体密度的变化不影响其在大鼠中抑制吗啡诱导的镇痛的功效。用于治疗酒精和阿片类药物依赖的缓释纳洛酮的临床试验目前正在进行中。
While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex(R)) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [H-3] DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [H-3] DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.