Characterizing the influence of structure and route of exposure on the disposition of dithiocarbamates using toluene-3,4-dithiol analysis of blood and urinary carbon disulfide metabolites.

Differences in the toxicities observed for dithiocarbamates have been proposed to result from the influence of nitrogen substitution, oxidation state, and route of exposure. To better characterize the fate of dithiocarbmates in vivoas a function of structure and route of exposure, rats were administered equimolar doses of carbon disulfide (CS2), N-methyldithiocarbamate, pyrrolidine dithiocarbamate, N,N-diethyldithiocarbamate, or disulfiram daily for five days, either po or ip, and sequential blood samples obtained. Protein dithiocarbamates formed by the in vivo release of CS2, parent dithiocarbamate, and protein-bound mixed disulfides were assessed in plasma and hemolysate by measuring toluene trithiocarbonate generated upon treatment with toluene-3, 4-dithiol (TdT). To aid in determining the bioavailability of CS2 from the administered dithiocarbamates, the urinary CS2 metabolites, 2-thiothiazolidine-4-carboxylic acid (TTCA) and 2-thiothiazolidin-4-ylcarbonylglycine (TTCG), were also determined. The levels of TdT-reactive moieties detected depended upon both the compound administered and the route of exposure. Parent dithiocarbamates, with the exception of disulfiram, were eliminated from blood within 24 h; but protein associated TdT-reactive moieties persisted and accumulated with repeated exposure, regardless of the route of exposure. N-Methyldithiocarbamate demonstrated the greatest potential to produce intracellular globin modifications, presumably through its unique ability to generate a methylisothiocyanate metabolite. Urinary excretion of TTCA and TTCG was more sensitive than TdT analysis for detecting dithiocarbamate exposure, but TdT analysis appeared to be a better indicator of in vivo release of CS2 by dithiocarbamates than were urinary CS2 metabolites. These data suggest that CS2 is a more important metabolite, following oral exposure, than are other routes of exposure, e.g., inhalation or dermal. In addition, data also suggest that acid stability, nitrogen substitution, and route of exposure are important factors governing the toxicity observed for a particular dithiocarbamate.     

1例输注头孢哌酮钠舒巴坦钠后饮酒致双硫仑样反应患者的护理

头孢哌酮钠舒巴坦钠系头孢哌酮钠与舒巴坦钠的混合制剂，因其抗菌谱广而广泛应用于呼吸道感染、泌尿道感染、败血症、骨骼及关节感染等。现将我科收治1例应用头孢哌酮钠舒巴坦钠后饮酒致双硫仑样反应的护理报告如下。     

纳洛酮治疗双硫醒反应的临床观察及护理

目的 探讨纳洛酮对双硫醒反应的治疗效果.方法 将48例双硫醒反应伴低血压患者随机分为治疗组(NLX)26例,对照组22例.两组均给予吸氧、静脉输液、补充能量、止吐等常规治疗,NLX组在常规治疗基础上静注纳洛酮.结果 NLX组早期BP、HR、R 等基本生命体征恢复明显优于对照组(P＜0.01),48h后心肌酶的升高明显低于对照组(P＜0.01).结论 纳洛酮可作为特效药用于双硫醒反应伴低血压患者,并有显著保护心肌作用.     

Effects on Rat Liver Acetaldehyde Dehydrogenases in Vitro and in Vivo by Coprine,the Disulfiram-like Constituent of Coprinus atramentarius

Abstract Coprine, the disulfiram-like constituent of the mushroom Coprinus atramentarius was found to inhibit the low-K_m acetaldehyde dehydrogenase in rat liver and to increase the acetaldehyde level in blood during ethanol metabolism in vivo. Coprine did not inhibit the low-K_m enzyme in vitro, but the hydrolytic product of coprine, 1 -aminocyclo-propanol, was a potent inhibitor both in vitro and in vivo. A rapid onset of inhibition was observed after administration of coprine and the inhibition was long-lasting. It is suggested that 1-aminocyclo-propanol is responsible for the inhibition caused by coprine in vivo.     

Learning the Language of Abstinence in Addiction Treatment: Some Similarities Between Relapse-Prevention with Disulfiram,Naltrexone, and Other Pharmacological Antagonists and Intensive “Immersion” Methods of Foreign Language Teaching

Relapse-prevention (RP) is an educational process. Learning to abstain from alcohol or opiates after years of dependence involves selectively suppressing old, maladaptive habits of thought and behavior and establishing new, adaptive ones. This process resembles foreign language (FL) learning. Effective FL teaching techniques are relevant to RP. Immersion, the most effective FL teaching method, discourages students from using their first language ab initio, requiring them to use the FL instead, however inexpertly. It resembles exposure and response-prevention for phobic or compulsive disorders. Supervised disulfiram aids RP by discouraging alcoholics from responding to real-life drinking cues in the language of excessive drinking, requiring them, ab initio, to practice new, alcohol-free responses. Supervised or depot naltrexone acts similarly in opiate dependence. We discuss the concept of antagonist-assisted abstinence.     

Disulfiram 联合Cu对耐药白血病细胞的作用及与JNK通路的关系

目的研究disulfiram(DS)联合Cu(DS/Cu)对耐药白血病细胞株HL60/ADM的逆转耐药作用及与JNK通路的关系。方法MTT法检测DS/Cu对HL60/ADM细胞的增殖抑制作用;选取DS/Cu对HL-60/ADM无明显杀伤作用的IC20值作为逆转浓度,MTT法检测IC20浓度DS/Cu联合不同浓度ADM处理24h后的IC50值;流式细胞仪检测阿霉素、DS/Cu单药及DS/Cu与阿霉素联合处理HL-60/ADM24h凋亡细胞比例的变化;Westernblotting检测c-jun表达的变化。结果DS/Cu对HL60/ADM细胞具有显著的增殖抑制作用,处理24hIC50为(1.11±0.025)μmol/L。HL-60/ADM细胞经IC20浓度(0.63μmol/L)DS/Cu处理24h后,ADM的IC50值从(7.69±1.87)降到(0.48±0.021)μg/mL,逆转倍数为15.95倍(P=0.003)。0.63μmol/L的DS/Cu、1.25μg/mL的阿霉素单药及上述浓度的DS/Cu联合阿霉素作用HL60/ADM细胞24h后,联合组凋亡细胞比例较DS/Cu或阿霉素单药组均显著增多(P<...     

双硫仑抗肿瘤作用及其机制研究进展

戒酒药双硫仑已有70多年临床应用的历史,其安全性得到了广泛验证.目前,大量细胞和动物实验研究结果表明,双硫仑可抑制多种人恶性肿瘤细胞增殖、迁移和侵袭,诱导肿瘤细胞死亡.二价铜离子可增强双硫仑的抗肿瘤效应.双硫仑的代谢产物与二价铜离子螯合,从多方面影响肿瘤细胞生物学功能,如使细胞内氧化还原反应失衡,活性氧水平上升,引起内...     

Coadministration of disulfiram and lorazepam in the treatment of alcohol dependence and co-occurring anxiety disorder: an open-label pilot study

ABSTRACT

Background: Anxiety is common among persons with alcohol use disorder during early abstinence from alcohol. Although benzodiazepines are effective for short-term treatment of anxiety, they are rarely used beyond acute detoxification due to concerns about misuse or interactions with alcohol. Objectives: We conducted an open-label trial to explore the effects of coadministering lorazepam and disulfiram to alcohol-dependent patients with anxiety disorder symptoms. The rationale for this model is to minimize the risks of the benzodiazepine, while also potentially enhancing adherence to disulfiram. Methods: Forty-one participants with DSM-IV alcohol dependence who also met syndromal criteria for anxiety disorder with or without co-occurring major depressive syndrome initiated treatment with lorazepam (starting dose 0.5 mg three times daily) and disulfiram (starting dose 500 mg three times weekly). Participants received 16 weeks of monitored pharmacotherapy with manualized medical management. Results: Adherence to treatment decreased steadily with time (85.4% at 4 weeks, 36.6% at 16 weeks). Participants showed significant increases in percent abstinent days during treatment and at 24 weeks follow-up. Large reductions in anxiety, depression, and craving were observed during treatment, and improvement remained significant at 24 weeks. Duration of adherence with disulfiram strongly predicted abstinence at 16 weeks. There was no evidence of misuse of lorazepam or dose escalation during the study. Conclusion: Lorazepam can be safely used for short-term treatment of anxiety in combination with disulfiram treatment of alcohol use disorder. However, it is not clear that making lorazepam dispensing contingent on adherence to disulfiram enhances retention in disulfiram treatment.     

Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders.

BACKGROUND: Disulfiram and naltrexone are approved by the Food and Drug Administration (FDA) for the treatment of alcoholism, but these agents have not been rigorously evaluated in dually diagnosed individuals. METHOD: Two-hundred and fifty-four patients with an Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at three Veterans Administration outpatient clinics. Randomization included assignment to one of four groups: 1) naltrexone alone; 2) placebo alone; 3) (open-label) disulfiram and (blinded) naltrexone; or 4) (open-label) disulfiram and (blinded) placebo. Medication compliance was evaluated using the Microelectric Events Monitoring System. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms, alcohol craving, g-GGT levels and adverse events. RESULTS: There was a high rate of abstinence across groups. Subjects treated with an active medication had significantly more consecutive weeks of abstinence and less craving than those treated with placebo, but there were no significant group differences in other measures of alcohol consumption. There was no advantage of the combination of both medications. CONCLUSIONS: These data suggest a modest advantage for the use of disulfiram and naltrexone for this group of dually diagnosed alcohol-dependent individuals but did not suggest an advantage in the combination.