芥子气的生殖毒性

日本遗弃在华芥子气是我国一大潜伏的环境危害,芥子气也仍然是最有可能被使用的化学毒剂之一。当前注重的主要是芥子气的急性毒性和中毒人员的临床救治,而对芥子气给环境造成的长期影响和中毒人员的远后效应关注不足。作为已知的致突变和致癌剂,芥子气的生殖毒性尚不明确,国内外目前的研究结果互相矛盾,直接影响了对芥子气长期环境影响的评估,有必要从分子机制层面进一步深入研究其遗传和生殖毒性。     

L-硝基精氨酸甲酯对大鼠芥子气中毒疗效的评价

芥子气是一种糜烂性毒剂 ,1917年首次在比利时作为化学战剂使用 ,第一、二次世界大战时期及两伊战争中均使用了芥子气。尽管全球禁止化学武器公约已经生效 ,但由于芥子气具有理化性质比较稳定、穿透性强、中毒途径多、消毒及防治都比较困难等特点 ,因而目前它仍是各国装备的主要毒剂之一 ,在现代战争中仍然有着十分重要的地位。芥子气能直接损伤组织细胞 ,在局部引起皮肤、眼和呼吸道粘膜的炎症、坏死 ,大剂量中毒时还能导致全身中毒。目前芥子气中毒的防治仍主要依赖于体外消毒和对症治疗[1,2 ] 。近年来 ,随着世界各国在这方面研究的不断…     

二巯基丁二酸钠对大鼠芥子气中毒的疗效观察

芥子气是一种糜烂性毒剂,具有强烈的细胞毒作用。它不仅对接触局部造成损伤,还可经多种途径引起全身吸收中毒,表现为造血组织、胃肠道、心血管、神经系统以及物质代谢等多方面受损,严重者导致死亡。由于芥子气中毒机理的复杂性,至今还未找到理想的抗毒剂。二巯基丁二酸钠（ＤＭＳＡＮａ）作为双巯基解毒剂,可能能“阻止芥子气对体内含巯基蛋白质和酶的作用,使之免受损伤并维护其正常功能,减轻芥子气的全身中毒效应。”本研究以Ｗｉｓｔａｒ大鼠为实验模型。在１ＬＤ芥子气条件下,应用二巯基丁二酸钠（ＤＭＳＡＮａ）为抗毒剂。…     

抗氧化天然产物对芥子气氧化损伤的保护作用

目的 观察丹参、知母提取物对芥子气中毒所致氧化损伤的影响,评价其对芥子气中毒的预防和(或)治疗效果。方法 (1) 细胞水平试验：乳腺癌细胞MDA-MB-231和血管平滑肌细胞(VSMC)与芥子气200 μmol·L^-1作用15 min;受试药为丹酚酸4 mg、知母黄酮16 mg（1∶4）或丹酚酸4 mg、知母黄酮8 mg（1∶2）溶于50 μl DMSO,无血清DMEM稀释至100和50 mg·L^-1。预防给药时,药物与细胞预孵2 h,然后染毒; 治疗用药时,细胞染毒后与药物孵育24 h。分别观察细胞存活率并检测MDA水平。(2) 整体动物试验：雄性SD大鼠随机分为正常对照组、中毒对照组、维生素C（200 mg·kg^-1）治疗组（阳性对照）、抗氧化剂低剂量治疗组、中剂量治疗和高剂量治疗组。芥子气染毒剂量为3.5 mg·kg^-1（70%LD₅₀）,皮下注射,1 h后给予治疗;按丹酚酸∶知母黄酮1∶4,每日ig给予30, 60和120 mg·kg^-1,连续7 d。观察大鼠生存状况,测定血清中MDA, GSH和SOD水平,并取肠、肝进行病理学检查。结果 不同浓度的提取物复方对芥子气细胞毒性均无预防作用,但有一定治疗作用;复方提取物对芥子气引起的细胞氧化损伤有一定防护效果。提取物复方可提高芥子气中毒动物存活率;对脂质氧化和SOD抗氧化体系无明显影响;但可剂量依赖性地恢复芥子气中毒后的GSH水平。结论 芥子气对SD大鼠引起的氧化损伤可能主要由GSH体系介导,丹参、知母提取物通过升高GSH水平,发挥抗氧化作用,进而起到抗芥子气中毒效果。     

芥子气诱导大鼠小肠上皮细胞的凋亡

芥子气是一种双功能烃化剂,易与细胞内ＤＮＡ、ＲＮＡ和蛋白质等大分子物质起烃化反应,中毒后可以引起机体组织细胞的损伤以至死亡。细胞死亡方式有凋亡和坏死两种,但芥子气引起细胞坏死方式国内外还很少报道。小肠粘膜分裂旺盛的上皮细胞对芥子气较为敏感,致死剂量芥子气中毒动物的死亡高峰出现在中毒后第４,５ｄ,其主要原因是由于肠道严重失水所导致的低血容量性休克所致。本实验以大鼠小肠上皮细胞（ＩＥＣ６）为体外实验细胞模型,研究不同浓度芥子气对ＩＥＣ６细胞生长的影响及其引起的细胞死亡的方式。采用胎盘蓝染色法,发…     

小白鼠致死量芥子气吸收中毒死因的探讨

小白鼠致死量芥子气吸收中毒死因的探讨杨进生张理汉郑凤仙郑德琪刘宝云＊军事医学科学院毒物药物研究所（北京１００８５０）芥子气吸收中毒后，机体分裂旺盛的细胞损伤较重，如造血组织及肠粘膜上皮细胞等。在非致死剂量吸收中毒条件下，造血组织损伤较为明显，骨髓细胞...     

芥子气眼部损伤研究进展

<正>芥子气是一种亲脂和烷化的化学糜烂性毒剂,以液滴态、雾态、蒸汽态长期储存。战争状态可通过多途径中毒,穿透能力强,病程长,易导致大量战斗减员和长期伤残。据资料记载,两伊战争中芥子气眼部损伤率高达77.61%～92.6%本文就芥子气体内代谢与毒理、眼部损伤的特征及角膜损伤的研究现状作一综述。1芥子气体内代谢与毒理作用     

骨髓移植对小鼠芥子气中毒的治疗作用

目的将骨髓移植应用于芥子气全身吸收中毒小鼠的治疗,探索芥子气中毒治疗的新方法。方法Balb/c小鼠sc芥子气20mg.kg-1染毒,建立芥子气诱导的造血系统抑制模型。染毒后4h、第1天和第2天3次尾静脉输注雄性小鼠骨髓细胞悬液(每次约1×106细胞),染毒后第3,5,7和10天取血和股骨,计数外周血白细胞和骨髓有核细胞。另一组实验小鼠在染毒后4h及次日2次尾静脉输注骨髓细胞的同时合并使用重组粒细胞集落刺激因子(G-CSF)74μg.kg-1,观察上述指标的变化。结果与模型组比较,骨髓移植组小鼠血白细胞数呈升高趋势,至第10天有显著性差异;骨髓有核细胞数量升高明显,从第5天起有显著性差异。伍用G-CSF后,早期即可显著升高白细胞数。结论骨髓移植可有效改善芥子气中毒引起的造血系统抑制。     

芥子气软膏的含量及配制方法探讨

芥子气软膏治疗银屑病,疗效确切.但芥子气为糜烂性毒剂,毒性大,腐蚀性强,若配制不当易造成医疗事故.芥子气软膏的含量及配制方法各不相同.我院从1991～1993年来照资料配制软膏,治疗318例银屑病,通过用药观察,探讨芥子气软膏的含量及配制方法.1.一般资料     

中药毒副反应的应对策略

目的为了预防中药毒副反应的发生。方法通过对有关中药毒副反应的文献进行综合分析,找出产生毒副反应的因素,确定有效的应对方法。结果引起中药毒副反应的因素有处方超量、炮制不合格、用法不当、久服蓄积中毒、配伍不合理等,这些因素引起肝毒性、肾毒性、神经毒性、生殖毒性等,应加强中药饮片质量与使用的科学化、规范化、法制化管理,防范中药毒副反应的发生。结论通过加强中药的科学管理,提高中医药人员的素质,大力开展中药药学服务,可以预防中药毒副反应的发生。     

Protection against 2-chloroethyl ethyl sulfide (CEES)-induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway

Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100 years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by ~ 3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin.     

家兔用于药物生殖发育毒性评价的研究进展

生殖发育毒性评价是药物安全性评价的重要组成部分。家兔属兔科兔形目,是药物生殖发育毒性评价的非啮齿类哺乳动物模型之一,但是其相关研究较啮齿动物少,对不同种属动物模型进行药物生殖发育毒性评价有助于提高风险评估的准确性。从生育力与早期胚胎发育毒性试验、胚胎-胎仔发育毒性试验、围产期发育毒性试验和体外生殖发育毒性评价等方面综述了家兔在药物生殖发育毒性评价中的研究进展,并探讨了家兔在药物生殖发育毒性评价研究中存在的问题及今后的发展方向,以期为今后研究提供参考。     

Analysis of thiodiglycol in urine of victims of an alleged attack with mustard gas

A procedure for the semi-quantitative determination of thiodiglycol, a metabolite of the vesicant mustard gas, in urine has been developed. Thiodiglycol was converted into mustard gas using concentrated HCl at temperatures close to 100 degrees C. The headspace of the solution containing mustard gas, was trapped on an adsorption tube filled with Tenax-GC which was subsequently analyzed by gas chromatography/mass spectrometry. Using 10 mL of urine, a detection limit of a few ng/mL of thiodiglycol was achieved. The procedure was applied to urine samples obtained from Iranian patients who were the alleged victims of an attack by chemical warfare agents (probably mustard gas). A number of control samples were investigated as well. Thiodiglycol was found in the urine of the Iranian patients in concentrations varying between 3 and 140 ng/mL. However, the detection of thiodiglycol in concentrations up to 55 ng/mL in control samples excluded the unambiguous verification of the use of mustard gas against the Iranian patients.     

我国生殖毒理学研究进展

我国生殖毒理学研究在 60年代以评价化学物致畸效应为主 ;70年代有关刊物详尽描述了致畸和繁殖试验的方法 ;80年代制定的法规将喂养繁殖试验、喂养致畸试验和传统致畸试验列为必做试验 ,并在致突变试验项目中列出睾丸生殖细胞染色体畸变分析和精子畸形试验 ;90年代的研究内容已由单纯致畸研究扩大至男 (雄 )性和女 (雌 )性生殖和发育毒理 ,在研究手段上由整体动物实验扩大至全胚胎培养、组织培养、细胞培养 ,并运用了分子生物学理论和技术。现从生殖毒性测试的发展、观测生殖毒性指标的进展、化学物生殖毒性研究进展等几个角度对我国生殖毒理领域的研究作一概述 ,并提出今后的研究动向将会以生殖细胞遗传毒性研究、拓宽研究对象以及开展环境内分泌干扰物的研究为主     

6-bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride: synthesis, chemical characterization, murine P388 antitumor activity, and bone marrow toxicity

6-Bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride has been synthesized, characterized, and evaluated for antitumor activity and bone marrow toxicity in mice. The 1D- and 2D-NMR studies show the compound to exist as a beta-anomer chair conformation (23%), alpha-anomer chair conformation (22%), and several equilibrating boat conformations or furanose forms (55%). A single ip LD10 dose of 15.0 mg/kg produced antitumor activity against the murine P388 leukemia superior to that achieved with an equitoxic dose of nitrogen mustard. In normal mice, this 15.0-mg/kg dose produced minimal depression of peripheral white blood cells and no significant decrease in absolute neutrophil counts. A reduction in toxicity was also demonstrated for human bone marrow CFU-GM, as compared with nitrogen mustard and L-PAM. This and other sugar-containing mustard compounds may represent a class of antineoplastic alkylating agents with reduced bone marrow toxicity.     

Attempted use of zinc in vivo to protect against nitrogen mustard toxicity in tumor-free and in L1210 leukemia-bearing female B6D2F1 mice.

The use of alkylating agents in treating cancer is limited by their toxicity to both normal and tumor tissue. Early in vitro studies indicated that zinc might be effective in mitigating this toxicity to normal tissue. The present studies were done to determine the capability of zinc to induce in vivo a protective response to an alkylating agent without also contributing to mortality. Tumor-free and L1210 leukemia-bearing female B6D2F1 mice were treated with zinc before administration of the alkylating agent nitrogen mustard. Protocols for administration route and frequency as well as the chemical formulation of the zinc were varied. The effect of a phytate-free diet was studied. Two parameters were used to determine the effectiveness of zinc in protecting animals from the toxicity of nitrogen mustard: the number of tumor-free mice that survived and an increase in the median life span of the tumor-bearing mice. The zinc-induction protocols used in these studies provided a limited degree of protection against nitrogen mustard toxicity in tumor-free female mice, but in tumor-bearing animals the protective response elicited with the protocols examined did not provide an appreciable therapeutic benefit.     

Investigating Prevalence and Pattern of Long‐term Cardiovascular Disorders in Sulphur Mustard‐exposed Victims and Determining Proper Biomarkers for Early Defining,Monitoring and Analysis of Patients’ Feedback on Therapy

Among the most readily existing chemical warfare agents, sulphur mustard (SM), also known as mustard gas, is the most commonly used agent owing to its ease of synthesis and stockpiling. Unprotected exposure mostly results in debilitation rather than lethal injuries, leaving an exposed victim incapacitated for days to even months. Although acute toxicity of sulphur mustard has been fairly established, the long‐term post‐exposure effects either chronic or short‐term but significant are still evolving. A total of 30,000 Iranian victims of the Iran–Iraq imposed war have now – after 30 years – formed the key population demonstrating long‐term effects from sulphur mustard exposure. Recent studies have shown that the prevalence of several long‐term cardiovascular disorders (CVDs) has significantly increased among SM‐exposed victims including coronary artery disorders (CAD), coronary artery ectasia (CAE), congestive heart failure (CHF) and myocardium abnormalities. The more important point is the lack of a determinant biomarker for early screening, recognizing, treating, monitoring and estimating exposed victims’ response to applied therapy. Additionally, unidentified risk factors significantly decrease the chance of a successful therapy and result in undesired failure of a comprehensive therapeutic strategy. In this MiniReview, we examined the literature in detail to evaluate relevant reports considering long‐term cardiovascular complications of SM, detecting possible risk factors and determining possible preventing events.     

Protection against systemic poisoning by mustard gas, di(2-chloroethyl) sulphide, by sodium thiosulphate and thiocit in the albino rat

The lethal effects of mustard gas, di(2-chloroethyl) sulphide, in the albino rat have been counteracted by Thiocit, a mixture of sodium thiosulphate and trisodium citrate in the ratio 10:1, administered intraperitoneally in a dose of 2.75 g./kg. Thiocit afforded complete protection against greater than the median lethal dose of mustard gas whether given 10 min. before or 10 min. after mustard gas and raised the LD50 of mustard gas by approximately three times. The protection appeared whether the total dose of Thiocit was given in one injection or serially over 30 min. The effective doses of sodium thiosulphate and of Thiocit in rats were of the order of 3.0 g./kg. Sodium thiosulphate alone and Thiocit have been administered in single doses by slow infusion, by stomach tube and in drinking water. Both have shown activity by all routes of administration, but activity was greatest by intraperitoneal injection. The use of Thiocit in conjunction with mustard gas therapy is suggested.     

Sulfur mustard toxicity: History,chemistry, pharmacokinetics,and pharmacodynamics

Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims.     

Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics

Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims.