| Purpose:1.Based on association rules,the medication rule and basic drug combinations of traditional Chinese medicine for external treatment of eczema were mined,and the effectiveness and safety of traditional Chinese medicine lotion for external treatment of chronic eczema were further evaluated by Meta analysis system.The above literature researches provided scientific basis for the clinical application of traditional Chinese medicine lotion for external treatment of chronic eczema.2.According to the results of the literature research in the first part,the medication rule and basic drug composition of traditional Chinese medicine for external treatment of eczema were suggested.This part was aimed at conducting a randomized controlled clinical trial of the patients of chronic eczema by using Sanzi Granules,a traditional Chinese medicine containing essential drug composition for external treatment of eczema.In order to evaluate the clinical efficacy of Sanzi Granules in treating chronic eczema patients,the patients were scored and statistically compared before and after medication in terms of observation indicators for skin main symptoms,eczema area and severity,itching degree,quality of life.The total effective rate was calculated and the occurrence of adverse events and local adverse reactions were observed.3.Established the rat model of chronic eczema and treated by Sanzi Granules.To explore the mechanism of Sanzi Granules in the external treatment of chronic eczema by skin lesions score,histopathological observation,number of mast cells and protein expresion of IFN-γ,IL-4,IL-17,Foxp3,p-p38 MAPK,p38MAPK,p-NF-κBp65,NF-κBp65 in skin lesion tissues.Materials and Methods:1 Literature research1.1 Mining the medication rule of traditional Chinese medicine for external treatment of eczema based on association rulesBy searching PubMed,Cochrane library,Clinical trials,CNKI,VIP,Wanfang Data Knowledge Service Platform,and Sinomed database,literatures on clinical trials of external treatment of eczema with traditional Chinese medicine were collected from the establishment of the database to January 1,2019.According to inclusion and exclusion criteria,the literatures were screened and the database on external treatment of eczema with traditional Chinese medicine was established.The traditional Chinese medicines that met the inclusion criteria were input into Microsoft Excel one by one and counted their frequency.The frequency,properties,taste,meridian tropism and external efficacy of high-frequency traditional Chinese medicines(frequency ≥ 20)were classified and counted.The Apriori algorithm of Rstudio 1.2.5042 software was used to analyze the association rules of high-frequency traditional Chinese medicines.1.2 Meta analysis of the effectiveness and safety of traditional Chinese medicine lotion for external treatment of chronic eczemaThe literature retrieval method was same with 1.1.The clinical trials of traditional Chinese medicine lotion for external treatment of chronic eczema were included,including randomized controlled trials and semi-randomized controlled trials.According to the method of RCT quality evaluation in Cochrane System Evaluation Manual 5.1.0,the methodological quality evaluation of the included literature wss conducted;Meta analysis was conducted using Rev Man 5.3 software.2 Clinical studyPatients with chronic eczema syndrome of "blood deficiency wind dryness syndrome" or "yin deficiency blood dryness syndrome" were selected from the dermatology outpatient department of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine.The patients were randomly divided into Sanzi Granules group(32 cases)and Qingpeng Ointment group(32 cases)by a random sequence generated through R language software.Sanzi Granules is an internal preparation of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine,used for the treatment of chronic eczema,skin itching,etc;Qingpeng Ointment is widely used clinically as a recognized traditional Chinese patent medicine for external treatment of chronic eczema.Both groups of patients were treated with external therapy on the basis of conventional oral medication.The oral medications were Runzao Zhiyang Capsules,taken three times a day with 4 capsules,and Levocetirizine Hydrochloride Tablets,taken once a day with 5mg;All patients were treated with silicone cream topically twice a day.The treatment group patients were treated with Sanzi Granules Lotion twice a day with wet compress;The control group patients were treated with Qingpeng Ointment twice a day for external use.The course of treatment was 4 weeks,with follow-up visits every 7 days.The observation indicators included the total effective rate,skin main symptom observation index score,EASI score,itching degree VAS score,DLQI score,adverse events and local adverse reactions.Two follow-up visits were conducted 15 and 30 days after treatment to evaluate the recurrence rate.3 Experimental studyForty male SD rats were divided into normal group,model group,Sanzi Granules group,and Qingpeng Ointment group using a random number table method,with 10 rats in each group.The rat models of chronic eczema were prepared by sensitization with 7%dinitrochlorophenylacetone solution,and after 7 days,challenge with a 0.7%dinitrochlorophenylacetone solution every 5 days.After each stimulation,rats frequently scratched and rolled due to intense itching.Gradually,erythema,papules or raised edematous erythema,exudation,scabs,scratches,blood scabs,desquamation,keratinization and hypertrophy appeared at the site of stimulation.After each stimulation,the skin lesions were recorded,scored,and statistically analyzed.After the 6th stimulation,the above-mentioned skin manifestations could be observed in the skin lesions of each group of rats,and the stimulation was stopped.After successful modeling,the rats were treated with medication,including wet application of normal saline in the model group,wet application of Sanzi Granules Lotion in the Sanzi Granules group,and external application of Qingpeng Ointment in the Qingpeng Ointment group twice a day for 10 consecutive days.After each medication,the erythema,papules/edema,epidermal exfoliation,exudation/scabs,and lichenization of the skin lesions were observed and recorded,and then performed scoring and statistical analysis.After the treatment,2% pentobarbital sodium were injected into the abdomens and the skin was taken from the lesions.HE staining method was used to observe the morphological changes of the skin tissues;The protein expression of IFN-γ and IL-4 in skin lesions were detected by immunohistochemical technique;The protein expression levels of IL-17,Foxp3,p-p38 MAPK,p38MAPK,p-NF-κBp65 and NF-κBp65 in skin lesions were detected by Western blot.Results:1 Literature research1.1 450 articles that met the standards were included,with a total of 482 prescriptions involving 260 traditional Chinese medicines,with Radix Sophorae Flavescentis being the most common;There were 40 kinds of high-frequency traditional Chinese medicines,with the main properties being cold,slightly cold and cool.The majority of the medicinal tastes were bitter and slightly bitter,with the liver meridian being the most common.The classification of external efficacy was led by heat-clearing drugs.According to the analysis of association rules,Radix Sophorae Flavescentis,Cortex Phellodendri,Fructus Cnidii,Kochia Scoparia and Cortex Dictamni constituted the basic combination of external treatment for eczema(support=0.1282),and the strong association rules showed that Radix Sophorae Flavescentis was the core traditional Chinese medicine in prescription compatibility for external treatment of eczema.1.2 A total of 31 clinical trials(25 RCTs and 6 quasi-RCTs)were included in the meta-analysis,including 2899 patients.The total effective rate of the traditional Chinese medicine lotion group was better than that of the western medicine group [RR=1.25,95% CI(1.18,1.33)],and the subgroup analysis for patients with different skin lesions showed that the effective rate of the traditional Chinese medicine lotion group was better than that of the western medicine group,and the differences were statistically significant;The recurrence rate was included in a total of 10 studies,involving 1063 patients.The total recurrence rate of the traditional Chinese medicine lotion group was lower than that of the western medicine group[RR=0.29,95% CI(0.20,0.43)],and subgroup analysis of patients with different skin lesions showed that the traditional Chinese medicine lotion group was lower than the western medicine group,with statistical significance for the differences.All studies did not report serious adverse events,and 10 of them reported specific situations of adverse reactions,with mild symptoms.2 Clinical StudyA total of 64 subjects were included in this study,with 3 cases were shed.Finally,61 cases were finally included in the analysis,including 31 cases in the Sanzi Granules group and 30 cases in the Qingpeng Ointment group.The results showed that:(1)There was no statistically significant difference in the total effective rate between the two groups of patients after 4weeks of treatment(P>0.05),indicating that Sanzi Granules group and Qingpeng Ointment group had similar efficacy in treating chronic eczema;(2)After treatment,the itching degree VAS score in the Sanzi Granules group was significantly lower than that in the Qingpeng Ointment group,and there was a significant statistical difference between the two groups(P<0.05 and P<0.01),indicating that Sanzi Granules group was significantly better than Qingpeng Ointment group in relieving itch degree;(3)There was no statistically significant difference in the EASI and DLQI scores between the two groups of patients after treatment(P>0.05),indicating that the Sanzi Granules group and the Qingpeng Ointment group had similar effects in improving the eczema area and severity and improving the quality of life of patients;(4)There were statistically significant differences in the skin main observation indicators,EASI,itching degree VAS and DLQI scores before and after 4 weeks of treatment between the two groups(P<0.05),suggesting that the two external therapies had a certain effect in the treatment of chronic eczema;(5)Patients in the two groups were followed up 15 and 30 days after the end of treatment,and there was no statistically significant difference in the recurrence rate between the Sanzi Granules group and the Qingpeng Ointment group at two time points(P>0.05).No serious adverse events were reported in either groups of patients,and all 3 patients reported spontaneous remission of local adverse events.3 Experimental study3.1 Skin lesions scoreBefore topical medication,in each group of the rats in the model group,the Sanzi Granules group and the Qingpeng Ointment group showed erythema,papules/edema,epidermal exfoliation,exudation/scabs and lichenization,with no statistically significant difference in skin lesions score(P>0.05).Compared with the eczema model group,the skin lesions scores of the Sanzi Granules group and the Qingpeng Ointment group were significantly reduced on the 6th,8th,and 10 th days(P<0.01).Compared with the Qingpeng Ointment group,there was no statistically significant difference in skin lesions score in Sanzi Granules group(P>0.05),indicating that the efficacy of Sanzi Granules in alleviating skin lesions is similar to that of Qingpeng Ointment.3.2 Pathological observation of skin tissues under light microscopyIn the normal group,the epidermis and dermis of the rat skin were intact without any abnormalities.In the model group,the epidermis showed hyperkeratosis and dyskeratosis,with significant thickening of both the granular and spinous layers,and collagen fibers became thicker.In the Qingpeng Ointment group and the Sanzi Granules group,the hyperkeratosis and hypokeratosis of rat epidermis,and the hyperplasia of granular layer and spinous layer were all found to be alleviated.3.3 Toluidine blue staining was used to observe the number of mast cells in skin tissuesCompared with the normal group,the number of mast cells in the model group significantly increased(P<0.01).Compared with the model group,the number of mast cells in the Qingpeng Ointment group and the Sanzi Granules group were significantly reduced(P<0.01).There was no statistically significant difference in the number of mast cells between the Sanzi Granules group and the Qingpeng Ointment group(P>0.05).3.4 Protein expression of IFN-γ and IL-4 in skin lesionsIFN-γ:Compared with the normal group,the expression of the model group was decreased(P<0.01);Compared with the model group,the expression of Qingpeng Ointment group was increased,but the difference was not statistically significant(P>0.05);Compared with the model group,the expression of Sanzi Granules group was significantly increased(P<0.01).There was no statistically significant difference between the Qingpeng Ointment group and the Sanzi Granules group(P>0.05).IL-4:Compared with the normal group,the expression of the model group was significantly increased(P<0.01);Compared with the model group,the expression of Qingpeng Ointment group and Sanzi Granules group were decreased(P<0.01);There was no statistically significant difference between the Sanzi Granule group and the Qingpeng Ointment group(P>0.05).3.5 Comparison of IL-17,Foxp3,p-p38 MAPK,p38MAPK,p-NF-κBp65,NF-κBp65 protein expression in skin lesionsIL-17:Compared with the normal group,the expression in model group was significantly increased(P<0.01);Compared with the model group,the expression of Qingpeng Ointment group was decreased(P<0.05);Compared with the model group,the expression of Sanzi Granules group was decreased,but the difference was not statistically significant(P>0.05).There was no statistically significant difference(P>0.05)between the Sanzi Granules group and the Qingpeng Ointment group.Foxp3:Compared with the normal group,the model group showed a significant decrease in protein expression(P<0.01);Compared with the model group,the protein expression of Qingpeng Ointment group and Sanzi Granules group were significantly increased(P<0.01);There was no statistically significant difference between the Sanzi Granules group and the Qingpeng Ointment group(P>0.05).p-p38MAPK/p38MAPK:Compared with the normal group,the protein expression in the model group was increased(P<0.05);Compared with the model group,the protein expression of Qingpeng Ointment group and Sanzi Granules group were decreased(P<0.05);There was no statistically significant difference between the Sanzi Granules group and the Qingpeng Ointment group(P>0.05).p-NF-κBp65/NF-κBp65:Compared with the normal group,the protein expression of the model group was significantly increased(P<0.01);Compared with the model group,the protein expression of Qingpeng Ointment group was significantly decreased(P<0.01);Compared with the model group,the protein expression of Sanzi Granules group was decreased(P<0.05);There was no statistically significant difference between the Sanzi Granules group and the Qingpeng Ointment group(P>0.05).Conclusion:1.The basic medication rule of external treatment of eczema with traditional Chinese medicine were found out by association rules;Meta analysis further confirmed that traditional Chinese medicine lotions had good clinical efficacy and safety in the external treatment of chronic eczema,while having a low recurrence rate.To a certain extent,these provided ideas and directions for clinical medication,and provided reference and basis for the research and development of new drugs.2.Clinical trials confirmed that the Sanzi Granules group had good efficacy in the external treatment of chronic eczema,with few local adverse reactions and mild symptoms.Its overall efficacy and improvement of eczema area and severity,and improvement of quality of life in patients were no different from Qingpeng Ointment group.The Sanzi Granules group had a better therapeutic effect than the Qingpeng Ointment group in improving the degree of itching in patients,and had clinical promotion value.3.Animal experiments confirmed that Sanzi Granules could inhibit hyperplasia of mast cells,up-regulate the protein levels of IFN-γ and Foxp3,and reduce protein levels of IL-4,IL-17,p-p38MAPK/p38 MAPK,p-NF-κBp65/NF-κBp65,so as to play a therapeutic role in chronic eczema.These results preliminarily revealed the mechanism of Sanzi Granules in treating chronic eczema. |
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