Williams K D, Lopachin R M, Atchison W D, Peterson R E
Neurotoxicology. 1986 Spring;7(1):33-49.
Daily administration of dithiobiuret (DTB, 1 mg/kg X 6 days, ip) produced delayed onset muscle weakness in rats as indicated by failure in a treadmill test. In nerve-muscle preparations from DTB-intoxicated rats neuromuscular toxicity was manifested as contractile fatigue during tetanic nerve stimulation. As muscle weakness developed, feed intake decreased and the animals lost body weight. Water intake was not altered during this time, but urine output was increased concomitant with the development of muscle weakness and resulted in a state of negative water balance. Daily administration of d-penicillamine (d-PEN) antagonized DTB-induced treadmill failure in a dose-dependent fashion. A daily dose of d-PEN (1 mMol/kg, ip) that completely antagonized treadmill failure also antagonized the contractile fatigue, reduced feed intake, weight loss and negative water balance caused by DTB administration. In rats already intoxicated with DTB, initiating daily d-PEN treatment or discontinuing further DTB administration, caused the animals to recover normal treadmill performance after a latent period of five days. A single dose of d-PEN (1 mMol/kg, iv) was not effective in reversing treadmill failure or contractile fatigue in rats already intoxicated with DTB. Thus, continuous daily administration of d-PEN was necessary for it to be effective. A single dose of d-PEN (1 m Mol/kg, ip) administered one hr after [14C]-DTB (1 mg/kg, ip) did not affect the plasma and tissue concentrations of DTB-derived radioactivity or their corresponding elimination kinetics. Cumulative urinary and fecal excretion of DTB-derived radioactivity were also unaffected by d-PEN administration as were the relative proportions of DTB and two of its metabolites, monothiobiuret and thiuret, in urine. Other agents that produced dose-dependent antagonism of DTB toxicity were diethyldithiocarbamate, disulfiram, cysteamine and 2,2'-dipyridyl. Considering the chemical and biological properties of DTB and its antagonists, a mechanism of antagonism involving an alteration of the thiol-disulfide and/or divalent metal cation status of motor axon terminals is postulated.
每日腹腔注射二硫代双缩脲（DTB，1毫克/千克，共6天）会使大鼠出现延迟性肌肉无力，这可通过跑步机测试失败来表明。在DTB中毒大鼠的神经肌肉标本中，神经肌肉毒性表现为强直神经刺激期间的收缩疲劳。随着肌肉无力的发展，采食量减少，动物体重减轻。在此期间，饮水量未改变，但尿量增加，同时伴有肌肉无力的发展，导致负水平衡状态。每日给予d -青霉胺（d - PEN）以剂量依赖性方式拮抗DTB诱导的跑步机测试失败。每日剂量的d - PEN（1毫摩尔/千克，腹腔注射）完全拮抗跑步机测试失败，同时也拮抗收缩疲劳、减少采食量、体重减轻以及DTB给药引起的负水平衡。在已经被DTB中毒的大鼠中，开始每日d - PEN治疗或停止进一步给予DTB，会使动物在五天的潜伏期后恢复正常的跑步机表现。单剂量的d - PEN（1毫摩尔/千克，静脉注射）对已经被DTB中毒的大鼠逆转跑步机测试失败或收缩疲劳无效。因此，d - PEN必须持续每日给药才有效。在[14C] - DTB（1毫克/千克，腹腔注射）后1小时给予单剂量的d - PEN（1毫摩尔/千克，腹腔注射），并不影响DTB衍生放射性的血浆和组织浓度或其相应的消除动力学。DTB衍生放射性的累积尿排泄和粪排泄也不受d - PEN给药的影响，尿液中DTB及其两种代谢产物单硫代双缩脲和硫脲的相对比例也是如此。其他对DTB毒性产生剂量依赖性拮抗作用的药物有二乙基二硫代氨基甲酸盐、双硫仑、半胱胺和2,2'-联吡啶。考虑到DTB及其拮抗剂的化学和生物学特性，推测拮抗机制涉及运动轴突终末的硫醇 - 二硫键和/或二价金属阳离子状态的改变。
