复方硫酸铝注射液局部注射的安全性实验评价

Experimental Studies and Evaluation on the Safety of Compound Aluminum Sulfate Injection

目的研究复方硫酸铝注射液新西兰兔肌肉注射后的局部刺激性和药物的全身吸收,并考察复方硫酸铝注射液犬膀胱壁肌层注射后膀胱壁的坏死和愈合情况,以评价该药的安全性。方法新西兰兔股四头肌注射复方硫酸铝注射液,观察局部刺激反应;耳静脉采血,采用等离子体质谱法测定血铝浓度,DAS药代动力学程序处理血药浓度数据。手术暴露犬膀胱内壁,注射给药后观察药物浸润范围及愈合情况,并行病理学检查。结果复方硫酸铝注射液兔股四头肌注射后局部呈极严重刺激反应,血铝浓度略有升高,但不明显,不能进行药代动力学参数分析。采用梯形法计算曲线下面积,平均AUC0-24为(2.93±1.82)mg·L-1·h(n=5),相对生物利用度约为2.77%。穿过膀胱壁肌层注射,会造成膀胱壁坏死,但坏死部位能够在4周内愈合。病理检查结果表明,注射1周后可见注射部位黏膜及浅肌层出血坏死,伴大量炎细胞浸润;3周后黏膜及浅肌层被增生的纤维组织取代,黏膜表面覆盖薄层未机化组织;4周后则可见黏膜及浅肌层被弥漫增生的纤维结缔组织取代,细胞密集呈梭形,束状排列。结论复方硫酸铝注射液局部注射使组织坏死,药物全身吸收量很低;膀胱壁对由本品所致的坏死有极强的愈合能力,不会产生大出血、穿孔等严重的不良反应。本品是一种安全的新制剂。

Aim To study the in situ stimulation effect of compound almninum sulfate injection after i. m. in rabbitquadriceps and dog bladder. The absorption of aluminum and the healing of the bladder wall were also studied to evaluatethe safty of the compound injection. Methods Compound aluminum sulfate injection was injected i.m. in quadriceps ofthe rabbits. The in situ stimulation effect was observed directly. Blood samples were collected at different time after injection, determined by ICP-MS assay and treated with DAS program. The compound injection was injected into dog bladderwall on surgery, and tissue necrosis as well as the healing of the bladder wall was observed macrographically or pathologically 1,3 and 4 weeks after surgery. Results Severe stimulation was observed after intra quadriceps injection of compoundaluminum sulfate injection. However, there was no obvious elevation of blood aluminum concentration after i. m. The average AUCo-24 was （2.93 ± 1.82） mg·L^-1. h, corresponding to a relative bioavailability of about 2.77 %. Injection in bladder muscle necmtized the bladder wall, but the necrosis would heal up within 4 weeks. The pathological inspection showedthat a huge number of inflammatory cells were seen 1 week after injection. Fibroblast showed up three weeks later, andtook place of the membrane and the facial muscle four weeks after injection. Conclusion Compound aluminum sulfate injection causes in situ necroses, however, bladder wall will heal up in 4 weeks after injection and there is no bleeding orperforation on the wall. Drug absorption is very low, hence it is safe to administrate the compound injection.