Satoh R, Yajima R, Morioka H, Inazu M, Goto K, Tanaka T, Omosu M, Kobayashi T
Pharma Research Laboratories, Hoechst Japan Limited.
J Toxicol Sci. 1990 Nov;15 Suppl 3:147-71. doi: 10.2131/jts.15.supplementiii_147.
As a series of safety studies of cefpirome sulfate (CPR), its local irritancy was examined in rabbits after the following treatments: intracutaneous injection (single), application into the conjunctival sac of the eye (single), intramuscular injection (single, 7-day repeated), and intravenous injection (8-day repeated). In addition, the hemolysis test was carried out with human blood. When CPR was injected intracutaneously at a high concentration of 20%, its irritating effects were only equal to or slightly stronger than those of distilled water for injection and Na2SO4 solution. The same concentration of the compound applied into the conjunctival sac had little irritancy to the eye. In the single intramuscular administration experiment, muscular changes caused by 10% CPR were comparable to those by 0.75% acetic acid, slightly severer than those by physiological saline, and slighter than those by 6% acetic acid at 2 days after administration, but at 7 days, the changes were apparently slighter than those by 0.75% acetic acid. CPR is classified under Grade 3 according to the draft guidelines for local tolerability studies issued by the Ministry of Health and Welfare of Japan. The repeated intramuscular administration experiment showed the following results. Muscular changes caused by 10% CPR were comparable to those by physiological saline and slighter than those by 0.75% acetic acid, 5% cefotetan (CTT) and 20% cephalothin sodium (CET) at 2 days after the last administration. At 7 days, the changes were slightly severer than those by physiological saline, but slighter than those by the other control solutions. Microscopically, a tendency toward recovery was marked. In the vascular irritancy experiment, the 10% CPR group showed thrombus macroscopically on and after day 5 of dosing. Microscopy at the end of the 8-day administration period revealed thrombus and organized thrombus. In the 20% CET group, thrombogenesis was slighter than that in the 10% CPR group, while perivascular changes were severer. The changes caused by 5% CTT (thrombogenesis, perivascular changes) were somewhat severer than those by 10% CPR. In the hemolysis test, 10% CPR solution applied to fresh blood from adult men caused to hemolysis when determined by the macroscopic or spectrophotometric method.
作为硫酸头孢匹罗（CPR）系列安全性研究的一部分，在兔身上进行了以下处理后检测其局部刺激性：皮内注射（单次）、滴眼（单次）、肌肉注射（单次、重复7天）和静脉注射（重复8天）。此外，还用人血进行了溶血试验。当以20%的高浓度皮内注射CPR时，其刺激作用仅等于或略强于注射用蒸馏水和硫酸钠溶液。相同浓度的该化合物滴眼对眼睛刺激性很小。在单次肌肉给药实验中，10%CPR引起的肌肉变化与0.75%乙酸引起的相当，给药后2天比生理盐水引起的略严重，比6%乙酸引起的略轻，但在7天时，变化明显比0.75%乙酸引起的轻。根据日本厚生省发布的局部耐受性研究指导方针草案，CPR被归类为3级。重复肌肉给药实验结果如下。末次给药后2天，10%CPR引起的肌肉变化与生理盐水相当，比0.75%乙酸、5%头孢替坦（CTT）和20%头孢噻吩钠（CET）引起的轻。7天时，变化比生理盐水引起的略严重，但比其他对照溶液引起的轻。显微镜下，恢复趋势明显。在血管刺激性实验中，10%CPR组在给药第5天及以后肉眼可见血栓。给药8天结束时的显微镜检查显示有血栓和机化血栓。在20%CET组，血栓形成比10%CPR组轻，而血管周围变化更严重。5%CTT引起的变化（血栓形成、血管周围变化）比10%CPR引起的略严重。在溶血试验中，用宏观或分光光度法测定时，10%CPR溶液作用于成年男性新鲜血液会引起溶血。
