Causative agent of vascular pain among photodegradation products of dacarbazine
Causative agent of vascular pain among photodegradation products of dacarbazine
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DOI：
10.1211/002235702320266280
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发表时间：
2002-08-01
影响因子：
3.3
通讯作者：
Miyamoto, K
中科院分区：
文献类型：
--
作者：
Asahi, M;Matsushita, R;Miyamoto, K
当静脉注射时，抗癌药物达卡巴嗪的光降解产物会引起不良反应，包括局部静脉疼痛。在这项研究中，我们试图确定这些产品中的哪一个是负责的。我们合成或购买了5种达卡巴嗪的光降解产物（二甲胺、5-重氮咪唑-4-甲酰胺（重氮-IC）、4-氨基甲酰基咪唑-5-油酸盐、5-氨基甲酰基-2-（4-氨基甲酰基咪唑-5-基偶氮）咪唑-5-油酸盐和2-氮杂次黄嘌呤），并使用腹部拉伸或收缩试验检测了腹腔给药诱导的小鼠疼痛反应。只有Diazo-IC以剂量依赖性方式明显诱导小鼠疼痛反应，其他产品均未引起疼痛反应。小鼠疼痛反应的阈值浓度估计约为0.1 mg mL（-1）。双氯芬酸钠可显著降低醋酸引起的小鼠疼痛反应，但对重氮-IC引起的疼痛反应无影响。这一结果表明，重氮-IC引起的疼痛的机制是不同的醋酸引起的炎性疼痛。达卡巴嗪本身以浓度依赖性方式产生大鼠胸主动脉条的显著松弛，但达卡巴嗪的活性与其光暴露溶液的活性之间没有差异，因此血管的收缩或松弛不太可能是疼痛反应的一个因素。总之，达卡巴嗪溶液光降解产生的重氮-IC导致静脉疼痛的副作用。不应使用已变成粉红色的达卡巴嗪溶液，因为重氮-IC是形成红色产物5-氨基甲酰基-2-（4-氨基甲酰基咪唑-5-基偶氮）咪唑鎓-5-醇盐的中间体。达卡巴嗪滴注制剂应避光。
The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate and 2-azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo-IC clearly induced pain reaction in mice in a dose-dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL(-1). While diclofenac sodium significantly reduced acetic-acid-induced pain reaction in mice, it did not influence those induced by Diazo-IC. This result suggests that the mechanism of Diazo-IC-induced pain is different from that of acetic-acid-induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration-dependent manner, but there was no difference between the activity of dacarbazine and its photo-exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo-IC generated by photodegradation of dacarbazine solution causes the side-effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo-IC is an intermediate in the formation of the reddish product, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate. Drip infusion preparations of dacarbazine should be shielded from light.