A Study On Intrathecal Methotrexate And Cytosine Arabinoside Contamintated With Trace Vincristine Adverse Events

[Objective] To find the cause of adverse event of administrating methotrexate and cytarabine. The clinical features, treatment effect and prognosis of the cases were systematically analyzed, who were victims of adverse effects of methotrexate and cytarabine.To reveal the problems underneath, provide recommendations and references for likely drug adverse effect events, and minimize the degree of risk of events alike.[Methods] We defined a case as onset from January1, to September30,2007, of bilateral flaccid paraparesis or paraplegia, or retention and incontinence of stool or urine, in a patient receiving intrathecal drugs. We used descriptive epidemiologic analysis to evaluate the distributions of the cases by person, time, and place, and calculated the attack rates and relative risks by various populations. The field investigation was used to Hualian Pharmaceutical Factory, and we collected the detailed information of drug production, Sources of raw materials and the drug transpotion.Using a retrospective cohort approach, we selected16hospitals from all that had reported cases. We used the ultra-high performance liquid chromatography to detect the contents of implicated drugs, including methotrexate and cytosine arabinoside, for vincristine, a contaminant drug that best describes the clinical and epidemiologic data. To clinical analysis and cluster analysis on147patients.To systematically review the case report of intrathecal vincristine administration. Subsequently, sampling was utilized to sample partly patients to follow up the prognostic situation and to estimate the effect factor of prognosis.[Results] As of the dateline in September17,2007, a total of192patients was enrolled to our case surveillance system of the severely adverse drug event. Among these patients, male is121, female is71. Most patients was under30years old, which accounts for76%. All patients were suffering leukemia, Lymphoma or choriocarcinoma patients. The adverse drug events case were onset from June12, to September11,2007. Among MTX070403A, MTX070405B, Ara-C070401A and Ara-C070401B, the attack rate were100%,76%,50%and42%, respectively. Low extremities muscle weakness (100%) difficulty in rising from a squatting poison(100%),musle power of lower extremities gradually reducing, complete flaccid paralysis(19.7%) and urinating and rectum dysfunction (59.2%) appeared in147cases.Vincristine production had immediately preceding production of the implicated lots in the same equipment.Using high performance liquid chromatography/coupled mass spectrophotometry, we detected vincristine (0.28-18μg) in unused vials from implicated lots of methotrexate and cytosine arabinoside. A dose-response relationship analysis between intrathecal injection vincristine and population attack rate were conducted, the results suggested the more higher concentration of intrathecal injection vincristine, the more relative risk of population attack rate.It is calculatede that the attack rate of the adverse drug event was1‰by BMDS software when intrathecal vincristine administration is0.02ug.A total of147patients were divided into three categories according to the diseases severity degree. A statistical analysis on the relationship between the content of intrathecal injection vincristine and severe degree of disease indicated the high level of drugs content is more than lower or middle level (F=8.06, P=0.00)The systematic evaluation on document of32case reports on inadvertent intrathecal injections vincristine shows surgical therapy using ventriculo-lumbar washout (χlog mnk2=11.49, P=0.00), using folic acid (χlog rank2=5.07, P=0.02) treatment and glutamate treatment (χlog rank2=7.47, P=0.00) could be improve the live time of patients.29patients were sampled in all subjects to carry out follow-up study, The results showed31%patients muscle strength recovery. however, the prognosis was still not satisfing:two died of primary disease,22suffered muscle wasting,9with complete flaccid paralysis,24was unable to walk. According to clinical analysis and cluster analysis on147patients, the results show low extremities muscle weakness, motor abnormalities, sensory disturbances, muscle wasting, urinating and rectum dysfunction appeared in147cases. The time from exposure to take place clinical symptoms the median days is16. A total of147patients were divided three categories according to the diseases severe degree.[Conclusions]①Methotrexate and Ara-C contaminated with the vincristine sulfate were cause of the drug adverse events.②The adverse event cases were with poor prognosis in the short-term. So positive measures should be actively and quickly carried on quickly to improve the prognosis of patients.