| Background:Mixed urinary incontinence(MUI)is a common disease,with a prevalence of 7.5-25%in the female population.The treatment of MUI is a challenge,because the patients often respond poorly to both pharmacotherapy and surgery,and there is a high recurrence rate.According to the guideline,behavioral therapy combined with pelvic floor muscle training and the pharmacotherapy for overactive bladder is usually the first-line treatment for women with MUI.However,due to patients’ poor compliance and adverse events related to the drugs,its clinical application is limited.Although the mid-urethral sling is a treatment option for patients with predominant stress component who have no response to first-line therapy,surgical treatment may aggravate the symptoms of urgency urinary incontinence(UUI)and ultimately leads to treatment failure.Therefore,it is extremally important to explore a safe and effective treatment for female MUI.Studies have confirmed that both acupuncture and Chinese herbal therapy can significantly improve the women’s clinical symptoms of MUI.However,it is still not clear whether the combination therapy with acupuncture and Chinese herb has a synergistic effect.This study attempted to explore the synergistic effect of acupuncture combined with Chinese herbal therapy,Yiqi Shuquan Decoction,in the treatment of MUI in women with Qi deficiency of spleen and kidney through a prospective,randomized,controlled clinical trial based on a factorial design.At the same time,network pharmacology has an advantage which can provide a variety of ideas and directions for basic research of traditional Chinese medicine.Objective:(1)To explore the therapeutic effects of Yiqi Shuoquan Decoction and acupuncture based on the formula of strengthening the spleen and nourishing the kidney on MUI in women.(2)To explore the synergistic effect of Yiqi Shuoquan Decoction and acupuncture in the treatment of female MUI.(3)Based on network pharmacology to explore the common target of Yiqi Shuoquan Decoction and MUI,excavate their biological processes and signaling pathways,so as to predict the mechanism,and build a "drug ingredient-target-action pathway" network to provide ideas for future research.Methods:This study is a prospective,randomized,controlled clinical trial based on a factorial design.Both the subjects and statistical evaluators are blinded in the study.All subjects in the study were MUI women with Qi deficiency of spleen and kidney who visited the Department of Urology of Guang’an Men Hospital from March 2018 to April 2021.Inclusion criteria were female patients(1)diagnosed as MUI for more than 1 year,(2)met the syndrome of TCM of Qi deficiency of spleen and kidney,(3)with age from 18 to 65 years,(4)with recorded more than 1 incontinent episode per 24 hours in their bladder diary,(5)provided written informed consent prior to participation.Exclusion criteria were patients(1)with other anatomical abnormalities,neurogenic diseases or other lower urinary tract diseases,such as spina bifida,overactive bladder,urethral stricture,(2)with previous anti-incontinence surgery,(3)taking medicine affecting on bladder function,(4)with severe internal diseases,(5)pelvic organ prolapse more than stage 2,(6)being allergic to the component of Yiqi Suoquan decoction,or with contraindication of acupuncture or anticholinergics,(7)during pregnancy or lactation period,(8)with limitation of motion or understanding,which limits the assessment of UI.Eligible subjects were randomly assigned to acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group,acupuncture plus placebo traditional Chinese medicine group or placebo acupuncture plus placebo traditional Chinese medicine group for 8 weeks of treatment.Among them,patients in acupuncture plus traditional Chinese medicine group received Chinese herbal granule,Yiqi Shuoquan Decoction,(30g of Astragalus,10g of Codonopsis,10g of Angelica,10g of Atractylodes,10g of Yizhiren,10g of Black Medicine,10g of Chinese Yam,10g of Chenpi,6g of Cimicifuga,Chai Hu 6g,raspberry 15g,stir-fried radish 10g),and acupuncture.The selected acupoints include bilateral Zusanli,Sanyinjiao,Zhongliao and Huiyang.After the needles were inserted into the acupoints,a portable electro-acupuncture machine was connected to the handles of needles in Zhongliao and Huiyang to provide the electrical stimulation with a density wave(4/20hz)for 30 minutes.The patients in acupuncture plus placebo Chinese medicine group received acupuncture plus placebo of Chinese herb granule.The patients in placebo acupuncture plus traditional Chinese medicine group received the placebo acupuncture plus Yiqi Shuoquan Decoction.The patients in placebo acupuncture plus placebo traditional Chinese medicine group was treated with placebo of Chinese herb granule plus placebo acupuncture.The primary endpoint of the study was the patient’s daily urine leakage as assessed by the 24-hour pad test.Secondary endpoints included:clinical symptoms assessed by ICIQ-SF questionnaire,frequency of urinary incontinence(UI)episodes assessed by 72-hour voiding diary,objective and subjective response rates of urinary incontinence,and patient quality of life assessed by I-QOL questionnaire.In addition,the adverse events and severity of adverse events in each group of patients during the study were recorded in detail,and the relationship between adverse events and treatment was evaluated.Through the TCMSP platform,a drug-ingredient-target network of Yiqi Shuoquan Decoction was established,and disease targets related to MUI/UI were obtained by using Genecards,Drugbank,TTD,Disgenet and OMIM databases.The common target information was imported into the STRING website for protein interaction analysis,and the intersection targets were imported into the enrichment analysis website DAVID for Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis.Results:Finally,a total of 133 patients completed the study.Of those,34 patients are in acupuncture plus traditional Chinese medicine group;33 patients are in placebo acupuncture plus traditional Chinese medicine group;33 patients are in acupuncture plus placebo traditional Chinese medicine group;32 patients are in placebo acupuncture plus placebo traditional Chinese medicine group.(1)Primary end point:After 8 weeks of treatment,the patients in the acupuncture plus traditional Chinese medicine group,the acupuncture plus placebo traditional Chinese medicine group,and the placebo acupuncture plus traditional Chinese medicine group presented a significantly reduction in daily urine leakage compared with the baseline(P<0.01),but ones in placebo acupuncture plus placebo traditional Chinese medicine group did not(P>0.05).Regarding the change of the patients’ urine leakage assessed by 24-hour pad test before and after treatment,patients in the acupuncture plus traditional Chinese medicine group,the acupuncture plus placebo traditional Chinese medicine group,and the placebo acupuncture plus traditional Chinese medicine group presented a more significant decrease which are 68.9±18.8,60.5±19 and 61.2±16.1 grams respectively,compared to the 10.6±27.5 grams in placebo acupuncture plus placebo traditional Chinese medicine group(P<0.01).Furthermore,a positive interaction was detected between acupuncture and Yiqi Shuoquan Decoction,which means acupuncture and Yiqi Shuoquan Decoction have a synergistic effect in reducing daily urine leakage.In addition,although acupuncture plus traditional Chinese medicine group seems to reduce the daily urine leakage more effectively,there is no significant difference when compared with the acupuncture plus placebo traditional Chinese medicine group,or the placebo acupuncture plus traditional Chinese medicine group.(2)Secondary end point:Improvement of clinical symptoms:After 8 weeks of treatment,the ICIQ-SF total scores in the four groups were significantly decreased compared to the baseline(P<0.01).In terms of the reduction range,the placebo acupuncture plus the placebo Chinese medicine group decreased by an average of 2 points.Although it showed a significant reduction compared to the baseline,it did not reach the minimum clinical efficacy difference(MCID)of 2.52 points,suggesting that the symptoms improvement in this group was limited.Compared with placebo acupuncture plus placebo traditional Chinese medicine group,acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group,and acupuncture plus placebo traditional Chinese medicine group had a more significant decrease in the ICIQ-SF total score(P<0.01),with an average decrease of 8.4,7.1 and 7.3 points respectively,which were much higher than MCID,suggesting that the three groups of patients had satisfactory improvement of clinical symptoms.In addition,compared with the placebo acupuncture plus traditional Chinese medicine group and the acupuncture plus placebo traditional Chinese medicine group,the acupuncture plus traditional Chinese medicine group showed a more significant decrease(P<0.01).At the same time,interaction analysis showed that there was also a positive interaction between Yiqi Shuoquan Decoction and acupuncture in improving the total score of ICIQ-SF(P<0.0001).Changes in the frequency of urinary incontinence episodes:After 8 weeks of treatment,based on the 72-hour urination diary,the acupuncture plus traditional Chinese medicine group,the placebo acupuncture plus traditional Chinese medicine group,and the acupuncture plus placebo traditional Chinese medicine group could significantly reduce urinary incontinence episodes(P<0.01).The median reduction in urinary incontinence episodes was 2(2),1.7(1)and 2(2)times,respectively.By contrast,the median reduction of urinary incontinence in placebo acupuncture plus placebo Chinese medicine group was 0.5(1.825),which was not significantly different from baseline(P=0.12).In addition,the interaction analysis found that there was also a positive interaction between Yiqi Shuoquan Decoction and acupuncture in reducing the frequency of urinary incontinence episodes(P=0.0045).Objective cure rate of urinary incontinence:After 8 weeks’ treatment,the objective cure rates of acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group,acupuncture plus placebo traditional Chinese medicine group and placebo acupuncture plus placebo traditional Chinese medicine group were 23.5%and 12.1%,14.7%,and 0%,respectively,which had the overall statistical difference(P<0.001).The results of pairwise comparison between the groups showed that the cure rate of the acupuncture plus traditional Chinese medicine group was significantly higher than that of the placebo acupuncture plus traditional Chinese medicine group(P<0.001).Although the cure rate of placebo acupuncture plus traditional Chinese medicine group and acupuncture plus placebo traditional Chinese medicine group was higher than the placebo acupuncture plus placebo traditional Chinese medicine group,the difference was not statistically significant(P>0.05).In addition,the objective effective rates of acupuncture plus traditional Chinese medicine,placebo acupuncture plus traditional Chinese medicine,acupuncture plus placebo traditional Chinese medicine,and placebo acupuncture plus placebo traditional Chinese medicine group were 85.3%,69.7%,67.6%,and 15.6%,respectively,which had the overall statistical difference(P<0.001).The results of pairwise comparison between groups showed that the effective rate of acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group and acupuncture plus placebo traditional Chinese medicine group was significantly higher than that of placebo acupuncture plus placebo traditional Chinese medicine group(P<0.001).Subjective cure rate of urinary incontinence:After 8 weeks’ treatment,the subjective cure rates of acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group,acupuncture plus placebo traditional Chinese medicine group and placebo acupuncture plus placebo traditional Chinese medicine group were 20.6%and 15.2%,11.8%,and 0%,respectively,which had the overall statistical difference(P<0.001).The results of pairwise comparison between the groups showed that the cure rate of the acupuncture plus traditional Chinese medicine group was significantly higher than that of the placebo acupuncture plus traditional Chinese medicine group(P<0.001).Although the cure rate of placebo acupuncture plus traditional Chinese medicine group and acupuncture plus placebo traditional Chinese medicine group was higher than that of placebo acupuncture plus placebo traditional Chinese medicine group,the difference was not statistically significant(P>0.05).In addition,the subjective effective rates of acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group,acupuncture plus placebo traditional Chinese medicine group,and placebo acupuncture plus placebo traditional Chinese medicine group were 67.7%,57.6%,61.8%,and 9.4%,respectively,which had the overall statistical difference(P<0.001).The results of pairwise comparison between groups showed that the effective rate of acupuncture plus traditional Chinese medicine group,placebo acupuncture plus traditional Chinese medicine group and acupuncture plus placebo traditional Chinese medicine group was significantly higher than that of placebo acupuncture plus placebo traditional Chinese medicine group(P<0.001).Evaluation of quality of life and adverse events:After 8 weeks’ treatment,the quality of life of patients in the four groups all improved.The I-QOL scores of the placebo acupuncture plus the placebo Chinese medicine group did not reach the MCID,suggesting that the improvement of the quality of life in this group was limited.Compared with the placebo acupuncture plus placebo traditional Chinese medicine group,the acupuncture plus traditional Chinese medicine group,the placebo acupuncture plus traditional Chinese medicine group and the acupuncture plus placebo traditional Chinese medicine group,all showed a more significant improvement in the I-QOL score(P<0.01),which were much higher than MCID,suggesting that these three groups of patients had a satisfactory improvement in quality of life.In addition,interaction analysis found that there was also a positive interaction between traditional Chinese medicine Yiqi Shuoquan Decoction and acupuncture in improving patients’ IQOL scores(P<0.0001).During this study,no serious adverse events occurred in the four groups of patients.Network pharmacology results:Six core targets were screened from the intersection targets of Yiqi Shuoquan Decoction and mixed urinary incontinence:TP53,IL6,CASP3,AKT1,TNF,JUN.The KEGG enrichment results showed that the intersection targets of Yiqi Shuoquan Decoction and mixed urinary incontinence were mainly enriched in the following pathways:pathways in cancer,AGE-RAGE signaling pathway in diabetic complications,prostate cancer,lipids and atherosclerosis Sclerosis,hepatitis B,bladder cancer,endocrine resistance,fluid shear stress and atherosclerosis,IL-17 signaling pathway,tumor necrosis factor signaling pathway,Kaposi’s sarcomaassociated herpesvirus infection,proteoglycans in cancer,chemical Oncogenic-receptor activation,hepatitis C,pancreatic cancer,human cytomegalovirus infection,PI3K-Akt signaling pathway,cellular senescence,colorectal cancer,platinum resistance,etc.Conclusion:Through a prospective,randomized,controlled clinical study based on a factorial design,we draws the following conclusions:(1)Both the traditional Chinese medicine Yiqi Shuoquan Decoction and acupuncture based on the strengthening spleen and nourishing the kidney method can significantly reduce the daily leakage of urine and the frequency of urinary incontinence in patients with mixed urinary incontinence,and these two treatments can both improve the clinical symptoms and quality of life of the patients.(2)The traditional Chinese medicine Yiqi Shuoquan Decoction and acupuncture based on the method of strengthening the spleen and nourishing the kidney have a synergistic effect in the treatment of female mixed urinary incontinence.(3)The network pharmacology analysis showed that the core targets of the intersection of Yiqi Shuoquan Decoction and mixed urinary incontinence were:TP53,IL6,CASP3,AKT1,TNF,JUN.The results of enrichment analysis also showed that the mechanism of Yiqi Shuoquan Decoction in the treatment of mixed urinary incontinence may be related to inflammation,proteoglycan,apoptosis and other pathways. |
PDF Full Text Request