Model Establishment And Drug Intervention For Infusion Phlebitis Induced By Vinorelbine

Infusion phlebitis is one of the common complication induced by clinical intravenous drug therapy,its incidence in patients which accepted intravenous drug therapy is up to 25%or more.The disease brings more extra pain and additional medical cost to patient.If this drug-induced disease is light,it may greatly interfer patients' medication compliance and quality of life,sometimes it even can make patients to give up treatment.If it is severe, it can deteriorate into thrombus,it may have the risk of pulmonary embolism,cerebral infarction and other fatal complications.However,pathogenesis of infusion phlebitis has not yet been clarified,there is little efficient and special way to prevent or cure this drug-induced disease.Vinorelbine is a new plants antineoplastic agents which has been put into practice in the 1990s.From 1990s up to today,vinorelbine is still the first-line chemotherapeutics recommended by NCCN guidelines(National Comprehensive Cancer Network Practice Guideline in Oncology-v.1.2007) for treating common malignant tumors such as breast cancer,nonsmall-cell lung cancer,meanwhile it is widely used to treat other malignant tumors such as ovarian cancer,lymphoma.However vinorelbine can lead to infusion phlebitis which appears from twenty eight percent to forty five percent and often can not be cured in a long time.Infusion phlebitis has not been effectively solved until now,which frightens a great number of patients.Frequent and intolerant phlebitis limited the use of this effective agent,so vinorelbine become a strong clinical response to chemotherapy drugs representative of phlebitis.The current study of infusion phlebitis mostly is clinical observation and causative factor analysis,and it lacks systematic mechanism study and the specific basic research. There is few basic research in foreign countries,which is only restricted to antibiotics,but not involved in chemotherapeutic agents;More which is only cell stimulation experiments, not involved in the study of drug intervention and lacks animal-oriented model.It is reported in the literature abroad that cimetidine,a classic antagonist to H₂ histamine receptor,showed a significant preventive effect from VIN inducing infusion phlebitis. However,this mechanism of cimetidine is not clear.Cimetidine is a classic antagonist to H₂ receptor,but in recent years it was found that it has many differents from the other new H₂ receptor antagonist.Including through the reduction of endothelial cell adhesion molecule E-selectin(CD62E) expression and inhibit a variety of malignant tumor growth, metastasis and improve survival in patients.The cell and animal model experiments are confirmed by Japanese scholars:CIM can inhibit cancer cell adhesion to endothelial cells and prevent metastasis by down-regulating E-selectin expression.Natori T found that cimetidine also significantly reduced the formation of vascular endothelial cell,and E-selectin and its mediated cell adhesion in the process of angiogenesis plays an important role.Similarly,CIM can prevent metastasis by blocking E-selectin expression.Do these two effects of CIM have a same mechanism?Based on the matters mentioned above,first set up an animal model of infusion phlebitis by VIN,observe the influence of various factors for infusion phlebitis and initially study the intervention effect of CIM.Then though using gene knockout mice, prove that there is correlation between the process of this kind of infusion phlebitis and the expression of E-selectin.Last using immunohistochemistry,ELISA and flow cytometry techniques respectively,qualitatively and quantitatively study the influence of vinorelbine, cimetidine and other H₂ receptor antagonist drugs for E-selectin expression.The study consists of there parts:Partâ… :The establishment of infusion phlebitis model induced by intravenous administration of vinorelbine in the tail vein of miceOBJECTIVE:to establish an experimental model for infusion phlebitis induced by vinorelbine in mice. METHODS:C57 mice as the experimental animals,studing various factors such as delivery speed,dose and drug concentration to optimize the experimental conditions, imitate the process of infusion phlebitis induced by vinorelbine in clinical drug treatment. Inject vinorelbine into the mice on its tail vein using automatic device.Take photos of the mice which have been given drug every 24 hours and observe the phlebitis conditions. Measure the degree of swelling of rat tail at fixed location,and compare groups with each other.After seven days get the mouse tail tissue near puncture point,then quickly fix the tissue in 10%formalin more than four hours,using 20%EDTA make the tissue decalcified for a week,last be maded into paraffin section for the further analysis.Make a record of diameter of mice every day,and then analyze the difference of each group.We graded and scored the histopathological changes according the degrees of loss of venous endothelial cells,inflammatory cell infiltration,edema and thrombus respectively.RESULTS:Swelling degree of the model group is up to 30%,the histipathological changes of mice treated by VIN was observed such as loss of venous endothelial cells, inflammatory cell infiltration,edema and thrombus.CONCLUSION:The mice model of infusion phlebitis induced by VIN are the clinical characters of infusion phlebitis,it can be used for experimental research.Partâ…¡:Observing interference effect of the three kinds H2 receptor antagonist drug for infusion phlebitisOBJECTIVE:To study the interference effect of the three kinds H₂ receptor antagonist drug used for infusion phlebitis induced by VIN.METHODS:C57 mice were randomly divided into blank group,model group,the cimetidine intervention group,famotidine and ranitidine intervention group,adopt vinorelbine injection to induce phlebitis by tail vein injection.Preparation of the model when the pre-intravenous drug intervention.To observe after administration of the daily incidence of phlebitis,measuring the degree of swelling of mice tail and observing the situation of the organization swelling and receding in time. RESULTS:CIM can obviously and effectively weaken the degree of infusion phlebitis caused by VIN.Compared with VIN group,there are statistically significant in grade six;while FAM and RAN the interference effect are not prefect.CONCLUSION:Cimetidine may not be through the inhibition of H₂ receptor antagonists to interfere infusion phlebitis caused by VIN.Partâ…¢:The effect of E-selectin expression for the infusion phlebitis interfered by CIMOBJECTIVE:To discuss whether the expression drug regulation of E-selectin by CIM is one of infusion phlebitis of the mechanisms of intervention or not.METHODS:Using EA.hy926 human vascular endothelial cells cultured,we investigated the expression and regulation by drugs of E-selectin on vessel endothelial cells by immunohistochemistry,ELISA,flow cytometry.Using ELISA method to analysis of the signaling pathway in this process.In addition,bring in E-selectin gene knockout mice to explore the E-selectin in the role of intervention.RESULTS:Immunohistochemistry results showed that E-selectin was expressed on micro-vascular endothelial cell after the stimulation of VIN.Measurement of the E-selectin on EA.hy926 plasmalemma was undertaken by flow cytometry technology.VIN can up-regulate,the expression of E-selectin is up to 169.76%(P<0.05);and CIM can down-regulate,the expression of E-selectin is up to 7.65%.Soluble E-selectin in culture medium of EA.hy926 cells were measured before and after the stimulation of VIN and other test drugs.Also,VIN can up-regulate and CIM can down-regulate the expression of E-selectin.In the gene knockout animal experiments,cimetidine doesn't intervene to mitigate the trend of phlebitis.CONCLUSION:E-selectin plays an important role in the pathogenesis of infusion phlebitis induced by VIN,CIM may intervene the formation of infusion phlebitis.In conclusion,a new animal model of infusion phlebitis was established to study the mechanism of infusion phlebitis.Using EA.hy926 cells in vitro,investigate the relationship between the degree of E-selectin expression and the intervention drugs.Initially study the influencing factors and mechanism of drug-induced infusion phlebitis,make a basis for clariting the signal transduction mechanism of drug-induced infusion phlebitis,and provide a target for the prevention and treatment of infusion phlebitis induced by vinblastine drugs. This research has great significance for in-depth studing the mechanism of drug-induced phlebitis and explore the treating drugs and these pharmacological mechanism.