鞘注微量长春新碱污染的甲氨蝶呤或阿糖胞苷不良事件研究

发布时间：2018-11-24 20:29

【摘要】：目的：查明甲氨蝶呤、阿糖胞苷不良事件的原因；描述甲氨蝶呤、阿糖胞苷不良事件病例的临床特点；初步评价病例治疗效果和预后情况；总结调查过程中发现的问题,为预防控制该类药物不良事件的发生提供重要参考。方法：通过建立监测系统,收集在2007年1月1日～9月30日期间进行鞘内注射治疗后出现双下肢渐进性无力、蹲立困难或有尿便功能障碍等症状的患者资料。采用描述流行病学方法分析不良事件的时间、人群、地点分布。对华联药厂进行现场调查,收集药品生产环节、原料来源和药品流向等资料。使用回顾性队列研究方法选取16家发生不良事件病例的医院内的鞘内注射化疗人群作为研究队列,收集研究对象的相关资料,计算不同人群的相对危险度。运用超高效液相色谱仪检测甲氨蝶呤和阿糖胞苷样品中长春新碱的含量。运用文献系统评价法对既往误行鞘注长春新碱的病例报道进行综合分析。使用聚类分析描述不良病例的临床特征和疾病严重程度。选择部分不良事件病例,对患者预后情况及其影响因素进行分析。结果：截止到2007年9月27日,甲氨蝶呤、阿糖胞苷不良事件监测系统共收集了192例患者。其中男性121例,女性71例。病例主要集中在30岁以下,占所有病例的76%,所有患者均为白血病、淋巴瘤和绒毛膜癌的患者。不良事件病例发病时间分布在2007年6月12日至9月11日之间。鞘注问题批号Ara-C070401B发病率最高,为100%；鞘注其它问题批号分别为Ara-C070401A、MTX070405B和MTX070403A,其发病率依次为76%、50%和42%。对147例不良事件患者进行了核实诊断,不良事件病例临床症状表现为双下肢乏力(100%),蹲立困难(100%),肌力减退性加重(100%),严重时完全瘫痪(19.7%),多数有尿便功能障碍(59.2%)。上海华联药厂将长春新碱、甲氨蝶呤和阿糖胞苷在同一生产线上生产。问题批号药品均在长春新碱之后生产。采集的样品中,问题批号药品均检测出长春新碱,含量在0.28～18ug之间。剂量反应关系分析结果显示：鞘注长春新碱剂量越高,人群发病率的相对危险度越高。由BMDS软件推算出当混入鞘内的长春新碱的剂量高于0.02ug时,不良事件发病率为1‰。对147例不良事件患者进行聚类分析,聚类分析将147例患者分成了轻中重型病例。对鞘注长春新碱的剂量与病情程度的统计分析结果显示鞘注剂量与病情严重程度有关(F=8.06,P=0.00) 对既往误行鞘注长春新碱事件的病例报道系统评价结果发现,外科治疗使用脑室-腰椎脑脊液灌注引流术(χlog rank2=11.49,P=0.00)、谷氨酸(χlog rank2=7.47,P=0.00)和叶酸(χlog rank2=5.07,P=0.02)可以提高患者的生存时间。 29例不良事件患者预后随访研究结果显示采取多重治疗方式后,38%的患者肌力有恢复,但是预后仍然不良：2死于原发病,22例肌肉萎缩,9例完全性截瘫,24例行走困难。结论：①木次不良事件的原因是问题批号的甲氨蝶呤和阿糖胞苷混入了微量长春新碱,患者鞘内注射后引起神经损害；②不良事件病例,短期预后不良,应积极采取一些措施改善病例预后。
[Abstract]:Objective: To find out the causes of the adverse events of methotrexate and absaccharin, and to describe the clinical features of the cases of methotrexate and absaccharin, and to evaluate the curative effect and the prognosis of the case. The problems found during the investigation are summarized. An important reference is provided to prevent the occurrence of adverse events in the control of the drug. Methods: Through the establishment of the monitoring system, the patients with double lower limb progressive weakness, difficulty in squatting, or dysfunction of the urine and the like were collected in the period from 1 January to 30 September 2007. Data. Time, population, location, Distribution. Carry out on-site investigation of Hualian pharmaceutical factory, collect drug production link, raw material source and drug flow direction, etc. Data. A retrospective cohort study was used to select the intraventricular injection chemotherapy population in 16 patients with adverse event cases as the study cohort, to collect relevant information from the study subjects, to calculate the relative risk of the different populations Determination of Vincristine in Methotrexate and Asaccharin Samples by Ultra-High Performance Liquid Chromatography Content: A comprehensive review of the case reports of previously misdirected vincristine with the literature system evaluation method Analysis. The clinical features and the severity of the disease were described using cluster analysis Degree. Select a part of the adverse event case and the patient's prognosis and its influencing factors Analysis. Results: As of 27-Sep-2007, a total of 1 was collected by the treatment system for methotrexate and Asaccharin adverse events. 92 patients, of whom 121 were male, 71 cases of women. The case was mainly concentrated under the age of 30, accounting for 76% of all cases, and all the patients were leukemia, lymphoma and villus. Patients with membrane cancer. The incidence of adverse events was distributed between 12 and September 2007 11 days. The highest incidence of Lot No. Ara-C070401B was the highest, with 100%. The number of other issues for the injection was Ara-C070401A, MTX070405B, and MTX070403A, with an incidence of 76%, 50, respectively.% and 42% of the 147 patients with adverse events were verified and diagnosed. The clinical symptoms of the adverse events were two lower limbs (100%), squat (100%), hypodynamia (100%), and severe total paralysis (19.7%), most of which had urinary dysfunction (5 9. 2%). The Shanghai Hualian Pharmaceutical Co., Ltd. Production on the same production line. The drug of the lot number is in the same production line. After vincristine production. In the collected samples, the problem lot number drug was tested for vincristine, with a content of The results of the analysis of the dose response showed that the higher the dose of vincristine, the higher the dose of vincristine. The higher the relative risk of morbidity. The incidence of adverse events was 1%. Cluster analysis was performed on 147 patients with adverse events, and the cluster analysis will be 1. 47 patients were divided into light and medium-duty cases. The statistical analysis of the dose and severity of the injected vincristine showed that the injection dose was related to the severity of the condition (F = 8.06, P = 0. 00) The results of the case report system evaluation of the new base event found that the surgical treatment was performed using a ventricular-lumbar spinal fluid perfusion drainage (log rank2 = 11.49, P = 0. 00), glutamic acid (log rank2 = 7.47, P = 0. 00), and folic acid (Prolog rank2 = 5.07, P = 0. 02) The survival time of the patient could be increased. The outcome of the follow-up study of 29 patients with adverse events showed that 38% of the patients had the recovery of the muscle strength after the multiple treatment, but the prognosis was still poor: 2 died in the original disease and 22 cases Muscular atrophy, 9 complete paraplegia, 24 routine walking difficulties. Conclusion: The cause of the adverse events is that methotrexate and Asaccharin of the lot number are mixed with a trace of vincristine, which causes nerve damage after intraoral injection of the patient; and case of adverse events.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R181.35

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