Clinical Observation And Mechanism Study Of Sanjin Tablets In The Treatment Of Acute Simple Lower Urinary Tract Infection(Lower Jiao Damp-heat Syndrome)

BackgroundUrinary Tract Infection(UTI)is a major cause of urology and antimicrobial use.UTI belongs to the category of "stranguria" in Chinese medicine.Uropathogenic Escherichia coli(UPEC)is the main pathogen of UTI.Antibiotic resistance is one of the threats to global health and multi-drug resistant organisms are a challenge for UTI management.In recent decades,drug resistance and multidrug resistance of UPEC is a clinical problem.The drug resistance of Quinolones is at the forefront,which is related to gene mutation.Traditional Chinese medicine treatment of UTI research showed an upward trend and played an important role in reducing the use of antibiotics or reducing the production of drug-resistant strains.Acute simple cystitis is the main type of UTI,which is a common clinical disease.Chinese medicine as an independent intervention or combination with antibiotics may help to treat the recurrence of infection.Sanjin tablet is a Chinese patent medicine commonly used in the treatment of acute simple lower urinary tract infection,which have analgesic and anti-inflammatory effects.In summary,the research group carried out a randomized,double-blind,positive drug,parallel control and multicenter clinical study on the treatment of acute simple lower urinary tract infection(lower jiao damp-heat syndrome).Retrospective study of clinical efficacy and urine samples based on clinical data.The corresponding clinical trials and the detection of related indicators of animal experimental samples were carried out to explore the mechanism of Sanjin Tablets treatment.Part Ⅰ Clinical Research of Sanjin Tablets in the Treatment of Acute Simple Lower Urinary Tract Infection(Lower Jiao Damp-heat Syndrome)Objective:To evaluate the efficacy of Sanjin Tablets in the treatment of acute simple lower urinary tract infection(lower jiao damp-heat syndrome)through randomized,double-blind,parallel controlled and multi-center clinical study.Through the detection of clinical urine samples,the correlation between drug treatment pain and related indicators was explored.Methods:The clinical data of 180 patients with acute simple lower urinary tract infection(lower jiao damp-heat syndrome)from April 2018 to December 2019 including Xiyuan Hospital of Chinese Academy of Traditional Chinese Medicine and other three centers were analyzed.Comparison of Sanjin Tablets,levofloxacin and combination therapy in clinical efficacy and safety,then the pain and recurrence related detection of urine samples were carried out to evaluate the feasibility of clinical application of related indicators.The propensity score matching was performed on the variables affecting the efficacy of the group and the data of each group were analyzed on the basis of the matching.The propensity score matching was performed on the detection indexes and influencing outcome variables before treatment,then the correlation between the two qualitative variables was cross(chi-square)analyzed on the basis of matching.Binary Logistic regression analysis was performed on the main factors affecting the efficacy of clinical outcomes as binary qualitative variables.The main factors affecting the efficacy of clinical outcomes were linear.Ridge regression analysis of quantitative data in line with collinearity.Results:1.Compared with levofloxacin,there was no significant difference in the cure of clinical symptoms,the abnormality of urine analysis and examination and the cure of comprehensive efficacy of Sanjin Tablets.Compared with combination therapy,the clinical symptoms of Sanjin Tablets were cured with statistical difference,urine analysis examination was cured,comprehensive curative effect was cured with significant statistical difference.Compared with levofloxacin,there was no significant difference in the cure of clinical symptoms of combined medication and there was significant difference in the recovery of urine analysis and comprehensive curative effect.2.Drug therapy to improve pain and Substance P change has no correlation.The effect of drug therapy on IL-5 level was not correlated with recurrence.Regression analysis showed that Substance P and IL-5 had no correlation with the severity of the disease,the quantitative grade of TCM symptom classification,the single grade of urinary urgency in overactive bladder,the pain grade,the urine white blood cell(urine sediment),the clinical symptom cure,the abnormal urine analysis and the comprehensive curative effect.Conclusion:1.Sanjin Tablets,levofloxacin and combination therapy can effectively treat acute simple lower urinary tract infection(lower jiao damp-heat syndrome).Sanjin Tablets and levofloxacin in clinical symptoms,urine,comprehensive curative effect no significant difference.Sanjin Tablets in clinical symptoms,urine,comprehensive curative effect is better than the combination therapy;levofloxacin is superior to combined therapy in urine and comprehensive efficacy.2.The changes of Substance P in urine after drug treatment can not well reflect the improvement of clinical symptoms of urinary pain.The change of IL-5 in urine after drug treatment cannot well predict the recurrence of urinary tract infection after comprehensive cure.Part Ⅱ Effect of Sanjin Tablets on Inflammation,Pain Related Pathways and Urinary Tract Barrier in the Treatment of Urinary Tract InfectionObjective:To establish animal models of acute urinary tract infection with classical Murine.Effect and Mechanism of Sanjin Tablet on Acute Simple Lower Urinary Tract Infection by Therapeutic Intervention System,to analysis of Sanjin Tablets and antibacterial drugs,combined drug differences.Methods:According to the weight sequence number,200 female C57BL/6 mice were randomly divided into normal group,model group,Sanjin Tablets group,levofloxacin group and combination group.Each group of 40 mice.50 μ L UPEC CFT073 containing ≥2×108 CFU was prepared by bacterial culture and turbidimetry.Bacterial suspension was injected into the bladder cavity of C57BL/6 female mice aged 6 to 9 weeks by urethral catheterization on day 1 and day 3.The success of modeling was determined by detecting urine UPEC CFT073 ≥ 104 CFU/mL.Acute urinary tract infection C57BL/6 female mice were intervened by Sanjin Tablets,levofloxacin and combination therapy.To explore the effects of drug treatment on bacteria colonization in vivo were analyzed from multiple perspectives of urine bacteria,bladder adhesion bacteria and bacterial colonies in bladder cells.To explore the effect of drug therapy on pathology and toxicity from histopathology and organ index.To explore the effects of drug treatment on inflammatory were analyzed from IL-1 β-p38MAPK-NF-κB and IL-1 β-TLR4-NF-κB.To explore the effect of drug treatment on pain was analyzed from IL-1β-TLR4-SP/NK1R.To explore the effect of drug therapy on tight junction protein in bladder mucosa epithelium was analyzed by electron microscope and protein expression.Results:1.After one day of drug intervention,Sanjin tablet,levofloxacin and combination therapy had no difference in inhibition and killing of urine bacteria.After 3 days and 5 days of drug intervention,levofloxacin and combination therapy had significant therapeutic effects on urine bacteria,bladder adhesion bacteria and bacterial colonies in bladder cells.Combination therapy was more effective in urine bacteria and bladder adhesion bacteria and levofloxacin was more effective in the treatment of bacterial colonies in bladder cells.Sanjin Tablet has therapeutic effects on urine bacteria and bladder adhesion bacteria,among which urine is the most obvious.2.Sanjin Tablets,levofloxacin and combination therapy for 3 and 5 days had repair effect and had no damage to the bladder.Levofloxacin had the best effect on histopathological recovery and the combination therapy was superior to Sanjin Tablets.3.Sanjin Tablets,levofloxacin,combination therapy for 5 days can effectively reduce the level of IL-1β,IL-10.Sanjin Tablets can effectively reduce IL-5 level.Sanjin Tablets,levofloxacin and combination therapy for 5 days could effectively reduce the expression of TRL4 and p38MAPK protein and increase the expression of NF-κB protein.It reduce Occludin,Claudin-2 protein gene and upregulate Occludin,Claudin-2 protein epithelial expression.It improve bladder mucosal epithelial tight junction and epithelial cell internal structure.However,the relative expression of NK1R and Substance P protein was not significantly improved.Conclusion:Sanjin Tablets,levofloxacin and combination therapy can all treat acute urinary tract infection,of which levofloxacin has the most obvious therapeutic effect.Sanjin tablet has the most obvious inhibition and killing effect on urine bacteria and has certain inhibition and killing effect on bladder adhesion bacteria.The efficacy of combination therapy is not as good as that of levofloxacin alone,which may be related to the expression of tight junction proteins.Sanjin Tablets,levofloxacin and combination therapy have no difference in improving pain indicators.Sanjin Tablets may reduce the immune response of bladder tissue and reduce allergic reactions.In summary,the clinical trials of Sanjin Tablets in the treatment of acute simple lower urinary tract infection(lower jiao damp-heat syndrome)have showed that Sanjin Tablets can effectively treat acute simple lower urinary tract infection(lower jiao damp-heat syndrome).The animal experiment of Sanjin Tablets in the treatment of acute simple lower urinary tract infection showed that levofloxacin had the most significant effect on acute simple lower urinary tract infection.The efficacy of combination therapy is better than Sanjin Tablets,but less than levofloxacin.There are differences between animal experiments and clinical efficacy may be due to the species difference between human and experimental animals and the difference of strain sensitivity.The mechanism analysis of clinical trials and animal experiments on Sanjin Tablets in the treatment of acute simple lower urinary tract infection(lower jiao damp-heat syndrome)will provide reference for the related research on the prevention and treatment of urinary tract infection by clinical Chinese medicine.