Tolerance to disulfiram induced by chronic alcohol intake in the rat.
Tolerance to disulfiram induced by chronic alcohol intake in the rat.
复制标题
大鼠长期饮酒诱导的双硫仑耐受性。
DOI：
10.1111/j.1530-0277.2008.00658.x
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Y. Israel
中科院分区：
文献类型：
--
作者：
L. Tampier;M. E. Quintanilla;Y. Israel
背景
双硫仑是一种用于治疗酒精中毒的醛脱氢酶抑制剂，当其摄入量由第三人监督时是一种有效的药物。然而，其治疗功效差异很大，部分原因是双硫仑是一种前药，需要转化为活性形式，并且因为它显示出广泛的副作用，这通常会阻止使用确保完全治疗效果的剂量。在这项大鼠临床前研究中，我们报告了长期摄入乙醇诱导的双硫仑耐受性的发展，这是双硫仑作用的另一个变异来源，可能具有治疗意义，我们还讨论了这种作用的可能机制。
方法
Wistar衍生的大鼠作为高乙醇饮用者（UCh B）世代繁殖，训练3天（A组）或30天（B组）在乙醇（10% v/v）或水之间进行选择，24小时内从2个瓶中免费获得。随后，两组动物均给予双硫仑或氰胺（另一种醛脱氢酶抑制剂），并测定该自由选择范例中的乙醇摄入量。还向动物施用标准剂量的lg乙醇/kg（i.p），并测量动脉血乙醛。
结果
双硫仑（12.5和25 mg/kg）和氰胺（10 mg/kg）显著抑制了仅3天乙醇摄入的动物（A组）的乙醇摄入量（高达60 - 70%）。然而，在饮用乙醇30天的动物（B组）中，这两种药物对抑制乙醇摄入均无活性。注射1 g乙醇/kg后，双硫仑和氰胺的动脉血乙醛水平分别达到150和300 μ M，无论动物先前摄入乙醇的时间长短，这些值几乎相同。
结论
高饮酒大鼠的慢性乙醇摄入导致对双硫仑和氰胺对乙醇摄入的厌恶作用的显著耐受，尽管存在持续高水平的血液乙醛。这些发现可能对使用双硫仑治疗人类酒精中毒有影响。
BACKGROUND
Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect.
METHODS
Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured.
RESULTS
Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals.
CONCLUSIONS
Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.
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影响因子：
5.8
作者：
MAYS, DC;NELSON, AN;LIPSKY, JJ
通讯作者：
LIPSKY, JJ
DOI：
10.1111/j.1530-0277.2006.00181.x
发表时间：
2006-09-01
影响因子：
3.2
作者：
Zimatkin, Sergey M.;Pronko, Sergey P.;Deitrich, Richard A.
通讯作者：
Deitrich, Richard A.
将心理社会治疗与药物治疗相结合来治疗酒精依赖。
影响因子：
2.9
作者：
Weiss,RogerD;Kueppenbender,KarstenD
通讯作者：
Kueppenbender,KarstenD
影响因子：
9.8
作者：
Chen, CC;Lu, RB;Yin, SJ
通讯作者：
Yin, SJ
DOI：
10.15288/jsa.2000.61.5
发表时间：
2000-01-01
期刊：
JOURNAL OF STUDIES ON ALCOHOL
影响因子：
--
作者：
Li, TK
通讯作者：
Li, TK