新阿片类药物

2020
06/16

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米勒之声
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阿片类药物作为一类强效镇痛药,在围术期有非常广泛的应用,对于癌痛患者也能极大地减轻患者的痛苦。

本文由“小麻哥的日常”授权转载

阿片类药物作为一类强效镇痛药,在围术期有非常广泛的应用,对于癌痛患者也能极大地减轻患者的痛苦。阿片类在强效镇痛的同时,也有一定的副作用,比如瘙痒,比如恶心呕吐等。但也有的合成类阿片类药物被用在别的用途,可能对人体有害,比如作为毒品的添加剂……发表在Neuropharmacology的最新文章Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats 介绍了新型阿片类药物U-47700在实验鼠上的药代学和药效学情况!

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摘要译文

新型合成阿片类药物 U-47700在雄性大鼠体内的药效学和药代动力学

新型合成阿片类药物在世界范围内的毒品市场上以海洛因的掺杂物形式出现或假冒止痛药的成分。3,4-二氯 -n-[(1r,2 r)-2-(二甲氨基)环己基]-n-甲基苯甲酰胺(U-47700)是一种非芬太尼合成阿片类药物,过量可致死。在这里,我们检测了老鼠体内 U-47700的药效学和药代动力学。雄性 SD大鼠在氯胺酮 /  赛拉嗪麻醉下,留置静脉导管和皮下温度收发器。一周后,给大鼠注射 u-47700 HCl (0.3、1.0或3.0 mg / kg)或生理盐水,注射后15、30、60、120、240、480分钟通过静脉导管抽取血液样本(0.3 ml)。每次采血时进行药效学评价,并用液相色谱-串联质谱法测定血浆中 U-47700及其代谢产物的浓度。U-47700引起剂量依赖的热板潜伏期的增加,ED50:0.5 mg / kg和全身僵硬,ED50 :1.7 mg / kg,而剂量达到3.0 mg / kg 可引起低体温。U-47700血浆浓度随剂量增加呈线性增加,最大浓度(Cmax)在15-38min时到达。N-desmethyl-U-47700和 N,N-didesmethyl-U-47700达到 Cmax 值的时间有所延迟,但与母体化合物的峰值时间持平。其药效与血浆 U-47700及其代谢产物有关。利用放射配基结合分析,U-47700对阿片受体具有高亲和力(Ki =11.1 nM) ,而代谢产物弱18倍以上。我们的数据显示 U-47700引起典型的阿片类药物效应,这种效应与母体化合物的血药浓度有关。鉴于其高效性,U-47700对无意中接触到药物的人类构成了巨大的风险。

关键词: 镇痛; 全身僵硬; 代谢物; 阿片类; u-47700。

原文摘要

Pharmacodynamics and Pharmacokinetics of the Novel Synthetic Opioid, U-47700, in Male Rats

Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. 3,4-Dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED50 = 0.5 mg/kg) and catalepsy (ED50 = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (Cmax) achieved by 15-38 min. Cmax values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.

Keywords: Analgesia; Catalepsy; Metabolites; Opioid; U-47700.

原始文献

Truver MT, Smith CR, Garibay N, Kopajtic TA, Swortwood MJ, Baumann MH. Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats [published online ahead of print, 2020 Jun 10]. Neuropharmacology. 2020;108195. doi:10.1016/j.neuropharm.2020.108195

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本微信公众平台所刊载原创或转载内容不代表米勒之声的观点或立场。文中所涉及药物使用、疾病诊疗等内容仅供参考。

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关键词:
阿片类,药物,药效

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