| Epidermal growth factor receptor inhibitors are becoming more widely used in clinical practice.They have become first-line drugs for lung adenocarcinoma with EGFR mutation,KRAS wild-type advanced colorectal cancer and so on.While prolonging the overall survival and progression-free survival,it also brought some more obvious adverse reactions.At present,rash is the most common adverse reaction,and its incidence rate is 50%-100%,which has become the most important factor affecting the quality of life of patients with advanced tumors.In the treatment of rash,most of the current western medicine mainly include antibiotics,hormones,but the effect is far from satisfaction,and it is easy lead to recurrence.In terms of Chinese medicine treatment,many studies have confirmed that the treatment effect and safety of Chinese medicine is better than Western medicine treatment.By summarizing the clinical manifestations of patients with rash,based on the basic theory of traditional Chinese medicine,combined with clinical experience,we invented "Zhi Yang Ping Fu Ye".Studies have confirmed that the drug has an effective rate of more than 9%for rashes with safety,which was included in the latest expert consensus.However,the mechanism of action of "Zhi Yang Ping Fu Ye" has not yet been elucidated,so this study is intended to explore the possible mechanism of action of "Zhi Yang Ping Fu Ye" on the basis of previous studies and combined with animal experiments.Further application provides more complete data supports.Objective.1.To establish an epidermal growth factor receptor inhibitor-associated rash animal model byinjecting intraperitoneally the Cetuximab.2.To establish an animal model of epidermal growth factor receptor inhibitor-related rash by taking Gefitinib or Erlotinib.3.To initially explore the mechanism of action of "Zhiyang Pingfuye" in treating epidermal growth factor receptor inhibitor-related rash.Method1.Intraperitoneal injection of cetuximab to establish an animal model of epidermal growth factor receptor inhibitor-related rashEighteen female SCID mice were randomly divided into blank control group,cetuximab high-dose group,cetuximab middle-dose group,cetuximab low-dose group,and saline control group.The blank group was not treated,and the cetuximab high,medium,and low dose groups were given intraperitoneal injection of cetuximab injection at 80 mg/kg,40 mg/kg,and 20 mg/kg doses,respectively.Saline is injected intraperitoneally;it is administered on a weekly,Wednesday,and Friday basis for a total of 4 weeks of intervention.After the experiment,the general skin performance and skin pathological performance of the mice were observed.2.Gefitinib and erlotinib were intragastrically established to establish an animal model of epidermal growth factor receptor inhibitor-related rashTwelve female BN rats were randomly divided into blank group,ovalbumin group,gefitinib group and erlotinib group.The blank group was not treated;the ovalbumin group was given an ovalbumin solution 1 mg/dose;the gefitinib group was given a gefitinib solution 37.5 mg/kg;the erlotinib group was given erlotib Nigros solution was given by intragastric administration at a dose of 23.5 mg/kg;the frequency of administration was once a day for 45 days.After the experiment,the gross skin performance and skin pathology of the mice were observed.ELISA was used to monitor the expression of TNF-α,IL-6 and other inflammatory factors in rat serum.3.Experimental Study on the Mechanism of Traditional Chinese Medicine "Zhi Yang Ping Fu Ye" in Treating Epidermal Growth Factor Receptor Inhibitor-Related RashesTwenty-seven female BN rats were marked on the tail with a marker.Randomly divided into blank group and gefitinib group.The blank group received no intervention;the gefitinib group was given gefitinib solution by intragastric administration at a dose of 37.5 mg/kg once a day for 21 consecutive days.After the gavage on the 21st day,the rats in the gefitinib group were regrouped and randomly divided into the gefitinib monotherapy group,gefitinib+topical "Zhi Yang Ping Fu Ye" group,and gefitinib+saline group.From the 22nd day,the mice in each group except the blank group continued to be fed with gefitinib 37.5mg/kg once a day;the gefitinib+topical "Zhi Yang Ping Fu Ye" group was applied externally on this basis The traditional Chinese medicine "Zhi Yang Ping Fu Ye",the dosage is 1.4ml/piece,once a day;the topical saline in the gefitinib+topical saline group,the dosage is 1.4ml/piece,once a day;continuous administration for 7 days.Observe the changes of rat skin morphology and skin tissue pathology.ELISA was used to detect the changes of inflammatory factors such as TNF-α and IL-6 in rat serum.Result1.After intraperitoneal injection of cetuximab,mice did not show typical rashes and scabs;skin pathology did not show obvious inflammation.2.In the gefitinib group,obvious skin rashes,scabs and exudation were observed,and a large number of inflammatory cell infiltration,keratinosis,spinous layer release and epidermal thickening were observed by HE staining of the skin.Morphological observation and pathological examination of skin of rats in blank group,ovalbumin group and Erlotinib group showed no obvious inflammation.In terms of IgE and TNF-α concentration,no significant difference was observed between the groups(P=0.061,P=0.057).In terms of IL-6,gefitinib group was significantly higher than the blank group,with a statistically significant difference(P=0.016),while erlotinib group was not significantly different from the blank group(P=0.910).3.The application of "Zhi Yang Ping Fu Ye" could significantly reduce the degree of skin inflammation in rats after 1 week,and the effective rate was significantly higher than that of saline(88.89%Vs 16.67%),and the difference between the two was statistically significant(P=0.001).In terms of serological indicators,the levels of TNF-α and IL-6 in the gefitinib single drug group were significantly higher than those in the blank group,and the differences were statistically significant(P<0.001).The level of TNF-α and IL-6 in the gefitinib+"Zhi Yang Ping Fu Ye" group were significantly lower than those in the gefitinib group(P=0.002,P=0.002)、The levels of TNF-α and IL-6 in gefitinib+"Zhi Yang Ping Fu Ye" were not significantly increased compared with the control group,and the differences were not statistically significant(P=0.279,P=0.165).The TNF-α index in the gefitinib+saline group was significantly higher than that in the blank group,and the difference was statistically significant(P=0.002),while no significant difference was found in the gefitinib single group(P=0.210).The level of IL-6 decreased compared with gefitinib group,with a statistically significant difference(P=0.029),while no significant difference was found compared with the blank group(P=0.064)。Conclusion1.Intraperitoneal injection of cetuximab cannot establish an epidermal growth factor receptor inhibitor-related rash model in SCID mice.2.Application of gefitinib can establish an epidermal growth factor receptor inhibitor-related rash model in BN rats;application of erlotinib cannot establish an epidermal growth factor receptor inhibitor-related rash model in BN rats.3.Traditional Chinese medicine "Zhi Yang Ping Fu Ye" can reduce the inflammation of rat back skin,which may play a role by down-regulating the expression of inflammatory factors such as TNF-and IL-6 in blood. |
PDF Full Text Request