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在阿片类药物依赖患者中,通过静脉注射或吸入途径给予高剂量药用海洛因的药代动力学和药效学。

Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients.

作者信息

Rook Elisabeth J, van Ree Jan M, van den Brink Wim, Hillebrand Michel J X, Huitema Alwin D R, Hendriks Vincent M, Beijnen Jos H

机构信息

Slotervaart Hospital, Department of Pharmacy and Pharmacology, Amsterdam, Netherlands.

出版信息

Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):86-96. doi: 10.1111/j.1742-7843.2006.pto_233.x.

Abstract

A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effect.

摘要

在荷兰,针对阿片类药物依赖患者开展了一项药代动力学-药效学研究,这些患者目前正在按照医疗处方接受高剂量的药用海洛因治疗。除了静脉注射海洛因外,还通过“追龙”法开具吸入用海洛因的处方。在这种方法中,海洛因碱在铝箔上加热,然后将海洛因蒸气吸入肺部。关于这种特定给药方法的药代动力学特征和生物利用度,人们了解得并不多。因此,开展了一项关于海洛因吸入和静脉使用的药代动力学和药效学研究。11名注射海洛因的患者和9名吸入海洛因的患者进入了该研究。他们接受稳定状态的海洛因治疗至少12个月。出于安全考虑,海洛因注射或吸入之间不存在交叉使用情况。在一项双盲随机研究中,向每位患者给予常规海洛因维持剂量的67%-100%-150%。海洛因的最大单次剂量为450毫克。使用液相色谱-串联质谱法分析血浆中海洛因及其代谢物6-单乙酰吗啡、吗啡和吗啡葡糖苷酸的浓度。评估血压、心率、皮肤温度和反应时间。此外,受试者对海洛因渴望程度和海洛因效果评价的视觉模拟量表进行评分。在吸入和注射海洛因的患者中,海洛因及所有检测到的代谢物的曲线下面积与海洛因剂量呈线性相关。吸入后,海洛因及其代谢物的平均C(max)比静脉注射后低2-6倍。海洛因吸入的生物利用度(F)估计为52%(95%可信区间44%-61%)。海洛因从血浆中迅速清除。静脉给药后,Cl/F为930升/小时(95%可信区间799-1061升/小时),吸入后为1939升/小时(95%可信区间1661-2217升/小时)。海洛因的清除率(Cl)和分布容积(Vd)与体重相关(R(2)为15%-19%)。吗啡葡糖苷酸水平与肌酐清除率呈负相关。给予海洛因后,注射海洛因患者的反应时间显著延长28±5.3毫秒,吸入海洛因患者延长13±4.9毫秒。给予海洛因后心血管变化仅为轻度。在两个给药组中,给予海洛因后渴望评分立即下降。尽管吸入海洛因后C(max)水平较低,但吸入海洛因患者对海洛因主观效果的评价比注射海洛因患者更积极。在这项双盲研究中,两个组中增加海洛因剂量比减少剂量更受青睐。常规海洛因剂量增加50%未引起任何严重副作用。

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