Short Course Digoxin in Acute Heart Failure by Nouira Semir in Open Access Journal of Biogeneric Science and Research

Short Course Digoxin in Acute Heart Failure by Nouira Semir in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Background
Despite many critical voices regarding its efficacy and safety, digoxin may still have a role in the management of heart failure. The objective of this study was to evaluate the efficacy and safety of a short course digoxin therapy started in the emergency department based on clinical outcome after 30 days post hospital discharge.

Methods
From Great Tunisian registry, acute decompensated heart failure (ADHF) patients from January 2016 to January 2018 were identified. Patients with incomplete data were excluded. Digoxin treated and non-treated patients were compared in a matched control study with respect to primary outcomes of all-cause mortality and HF readmission. Secondary outcomes included changes of cardiac output (CO) and left ventricular ejection fraction (LVEF) after 72 hours of hospital admission.

Results
The study population comprised 104 digoxin treated and 229 matched non-treated with a median age of 67.4±12.8. After 72 hours of ED admission, there was a larger increase of CO (17.8 % vs 14%; p=0.015) and LVEF (14.4% vs 3.5%; p=0.003) in digoxin group compared to control group. At 30-day post-hospital discharge 34 (10.2%) patients died and 72 (21.6%) patients were readmitted. Use of digoxin was associated with decreased risk of death and hospital readmission [odds ratio, 0.79 (95% CI, 0.71-0.89)].

Conclusion
In ADHF patients, treatment with digoxin was associated with a significant decrease risk of 30-day mortality and hospital readmission with an improvement of cardiac output and left ventricular ejection fraction.

Key words: Acute heart failure; digoxin; mortality; rehospitalization; emergency department.

INTRODUCTION

Heart failure (HF) is a major worldwide health problem and one of the most important causes of hospital admissions [1,2]. These hospitalizations are responsible for an important economic burden and are associated with high mortality rates, up to 20% following hospital discharge [3,4]. Acute decompensated HF (ADHF) management is difficult given the heterogeneity of the patient population, incomplete understanding of its pathophysiology and lack of evidence-based guidelines. Although the majority of patients with ADHF appear to respond well to initial therapies consisting of loop diuretics and vasoactive agents, these first line treatments failed to decrease post-discharge mortality and readmission rate [5,6]. Investigations of novel therapies such as serelaxin did not show a significant clinical benefit. In a recent multicenter, double-blind, placebo-controlled trial including patients who were hospitalized for acute heart failure, it was shown that the risks of death at 180 days were not lower in patients who had received intravenous serelaxin for 48 hours than in patients who had received placebo [7]. Numerous other clinical trials have been published on ADHF treatment and their results were disappointing in term of efficacy and/or safety [8-11]. Digoxin is one of the oldest compounds in cardiovascular medicine but its beneficial effect is very controversial [12]. Yet, digoxin has many potential beneficial properties for heart failure as it is the only oral inotrope available that did not alter blood pressure neither renal function. Despite its useful hemodynamic, neurohormonal, and electrophysiological effects in patients with chronic congestive HF, concerns about digoxin safety were constantly highlighted [13]. Consequently, the use of digoxin has decreased considerably, in the last 15 years [12]. Digoxin under prescribing is problematic for several reasons. First, it underestimated the substantial beneficial effect of digoxin on the reduction of hospital admissions in HF patients. Second, for its low cost, the favorable cost-effectiveness ratio of digoxin is highly desirable in low-income countries. Moreover, the question whether a short course of digoxin is useful in ADHF was not previously investigated in the era of new heart failure therapies including β-blockers, angiotensin converting enzyme inhibitors and angiotensin-receptor blockers [12]. The objective of this study is to assess the efficacy and safety of a short course digoxin in patients admitted to the ED with ADHF (Figure1 and Figure 2).

Figure1 :  Patients inclusion/exclusion Flowchart

£p=0.015 vs baseline, * p=0.003 vs control group.

Figure 2 : Cardiac output (CO) and left ventricular ejection fraction (LVEF) change from baseline at 72 hours in digoxin (DIG) and control groups.

PATIENTS AND METHODS

Data Source

We conducted a retrospective matched case-control study to assess the association between digoxin treatment and 30-day outcome in patients with ADHF. The ADHF patients were identified from the Great Tunisian database between January 2016 and January 2018. The patients included are residents of a community of 500,000 inhabitants in the east of Tunisia, served by 2 university hospitals (Fattouma Bourguiba Monastir, and Sahloul Sousse). ADHF was defined as an acute onset of symptoms within 48 hours preceding presentation, dyspnea at rest or with minimal exertion, evidence of pulmonary congestion at chest radiograph or lung ultrasound, NT-proBNP ≥1400 pg/ml. This electronic medical recording system provided detail of each patient admitted to emergency department (ED) for acute undifferentiated non traumatic dyspnea.

Study Population

Patients were included if the following data are available: demographic characteristics, comorbidities, current drug use, baseline NYHA functional class, physical exam findings, standard laboratory tests, brain natriuretic peptide levels at ED admission; echocardiographic results, bioimpedance measured cardiac output at ED admission and at hospital discharge, digoxin daily dose, 30-day follow-up information including ED readmission and survival status. A patient who received at least 0.25 mg of oral digoxin (1 tablet) for three days during hospital stay was defined as case; those who did not receive digoxin treatment were selected as control. The protocol used in this study was approved by the ethics committee of our institution, and all subjects gave their written informed consent to be included in the data base. All the listed criteria have to be fulfilled for patient’s inclusion. Exclusion criteria included ongoing treatment with digoxin, pregnant or breast-feeding women, patients with known severe or terminal renal failure (eGFR<30 ml/min/1.73m2), alteration of consciousness (Glasgow coma score <15) and patients needing immediate hemodynamic or ventilatory support. Cases were matched first for sex, then for age (±2 years) and NYHA functional class. We performed an individual matching; we matched each patient under digoxin (case) with 2 patients who did not receive digoxin (control) for age, gender and New York Heart Association (NYHA) classification. Reviewers were limited to matching criteria data only (e.g., blinded to 30-day outcomes) to eliminate potential sources of bias. Patients who were treated with digoxin and those who did not receive digoxin were clinically managed the same way.

Outcome Measures

The main end points included death or rehospitalization within 30 days after hospital discharge, and 30-day combined death-rehospitalization outcomes. Secondary end-points included CO change from baseline and length of stay in the hospital during the index episode.

Statistical Analysis

Baseline characteristics were compared between groups to detect any differences between cases and controls; independent t-tests were performed for normally distributed variables; Mann Whitney U tests were performed for continuous non-normally distributed variables; and chi square analyses were performed for categorical variables. Logistic regression analysis was performed to identify the odds ratios (ORs) and 95% confidence intervals (95% CIs) for hospital readmission and/or death risk with respect to digoxin treatment. Data are reported as means ± standard deviations, unless otherwise noted, and a p-value less than 0.05 via two-sided testing was considered statistically significant. Data were analyzed using the statistical software package SPSS version 18.

RESULTS

The initial study population comprised 1727 participants who were registered in the database. From this initial population, we excluded 956 with non-cardiac cause of dyspnea, and 211 with incomplete data. From the remaining patients, 104 were included in the digoxin group and 229 in the control group. Digoxin was orally administered once a day and almost all of our patients received the same dose (0.25 mg, one tablet) each day during at least three days. Only few patients received a lower (0.125 mg) or a higher (0.5mg) dose. Baseline characteristics of both groups are shown in table 1. Demographic characteristics were comparable among both study’s groups. There were no relevant differences in age, sex, or NYHA classification. The NYHA class collected was related to base line medical status (within three months before the ongoing exacerbation). Cardiovascular medical history was comparable for both groups. There were no significant differences between cases and controls regarding underlying other comorbidities. Fifty-two percent of the patients had ischaemic cardiomyopathy as the primary aetiology of their heart failure (47-57%) (Table1). Principal baseline medication consisted of diuretics, angiotensin converting enzyme-inhibitors, beta-blockers, and nitrates. Mean vital signs values at baseline were comparable among the 2 groups with respect to heart rate, respiratory rate, and blood pressure. NT-proBNP levels ranged from 1412 to 8615 pg/ml between; 61% in digoxin group and 59% in control group had reduced LVEF (<45%) (p=0.77). After 72 hours of ED admission, there was a larger increase of CO (17.8% vs 14%; p=0.015) and LVEF (14.4% vs 3.5%; p=0.003) in digoxin group compared to control group (Figure 1); NTpro BNP levels decreased and in digoxin group (2%) and in control group (1.2%) but the difference was not significant (p=0.06). Digoxin treatment was associated with a reduced length of hospital stay (10.1±7.2 days versus 6.6± days; p<0.01). At 30-day follow-up, digoxin group showed a significantly lower all-cause (p=0.04) and heart failure (p=0.02) hospital readmission rate compared to control group, and lower mortality (11.8% versus 6.7%; p=0.03) (Table 2). Digoxin treatment was found to significantly decrease the odds for the combined events of mortality and hospital readmission [odds ratio, 0.79 (95% CI, 0.71-0.89)]. No major side effects were observed in relation to digoxin therapy.

Table 1: Baseline characteristics of both study groups

IQR: interquartile range

*NYHA related to base line medical status (within three months before the ongoing exacerbation)

Table 2: Clinical outcomes

DISCUSSION

Our results demonstrated that digoxin is associated with a lower risk of 30-day hospital readmission among ED patients with decompensated HF. Compared with control group, LVEF and cardiac output increased and length of hospital stay decreased significantly in digoxin-treated group. Most available studies analyzed long-term effect of digoxin in patients with chronic heart failure, but data on the effect of short course digoxin on early clinical outcome and physiological related parameters in patients with acute heart failure are scarce. The concordance between physiological and clinical outcomes was in favor of the validity of our results. Digoxin is one of the oldest drugs used in cardiology practice, and few decades ago, it was prescribed in more than 60% of heart failure patients in the United States [14]. Digoxin is the only inotropic drug known to increase cardiac output and to reduce pulmonary capillary pressure without increasing heart rate or lowering blood pressure in contrast to other oral inotropes. However, despite the evidence of its beneficial effects on hemodynamic, neuro-hormonal and electrophysiological parameters, a great concern regarding its safety profile has been raised and the use of digoxin has declined significantly over the past two decades [15]. Indeed, in the ESC guidelines (2016), digoxin indication was limited only to patients with AF and rapid ventricular rate [16]. This could be understandable given the scarcity of randomized trials specifically aimed at testing digoxin safety in heart failure patients. The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a significant reduction in heart failure hospitalizations [17]. Most of the identified studies against the use of digoxin had many potential sources of bias requiring careful assessment. In fact, digoxin safety concern comes from very heterogeneous studies and non-experimental observational studies carrying a high risk of misinterpretation [18-20]. A recent study concluded that prescription of digoxin is an indicator of disease severity and not the cause of worse prognosis which means that a significant prescription bias might be caused by the fact that sicker patients, having a higher mortality risk receive additional treatment with digoxin [21]. Currently, in DIG trial, there is no evidence of an increased risk with digoxin treatment. Importantly, DIG trial demonstrated that beneficial digoxin effects were mainly observed in patients with HFrEF and those with serum digoxin concentration ≤0.9ng/ml. Digoxin efficacy may be attributed in part to the neurohormonal‐inhibiting properties of digoxin, especially in lower doses; it may also be related to its synergistic effects with beta-blockers as pro‐arrhythmic effects of digoxin would be expected to be attenuated by β‐blockers [22].

Our study has several limitations. First, as this is a retrospective analysis, we should clearly highlight that our results only describe associations and not causality. Second, our study is limited by its small sample size. Third, as in all case control studies; bias due to unmeasured confounders remains possible. We should have used the propensity-score matching to better match our two groups but we should point out that most of confounding variables influencing outcome were well balanced between the 2 groups of our study. Third, we had no data regarding post-discharge adherence to prescribed treatment nor we had informations on neither serum digoxin concentration nor the incidence of digoxin toxicity. We acknowledge that this important information would be a valuable support to our findings in demonstrating a correlation between serum digoxin levels and their clinical outcome in our patients. In addition, in our study only 30% of our patients were receiving aldosterone antagonists, and none were receiving cardiac resynchronization therapy, which may limit generalizability of our results.

CONCLUSIONS

Our findings provided an additional data to support the association between use of digoxin and clinical benefit in HF patients with reduced LVEF. Digoxin may potentially serve as an inexpensive tool for the reduction of short-term mortality and hospital readmissions which is an important objective especially in low-income countries in the health system.

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Noise Pollution is One of the Main Health Impacts in Big Cities Today by Tamaz Patarkalashvili* in Open Access Journal of Biogeneric Science and Research

Noise Pollution is One of the Main Health Impacts in Big Cities Today by Tamaz Patarkalashvili* in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Noise pollution today is one of the biggest health risks in big cities along with air pollution. It must be admitted that noise pollution was overlooked by scientists and city authorities lately. Noise pollution has adverse effect on all living organisms. Scientists confirm that noise incentives central nervous system that stimulus to release some hormones which increases risk of hypertension. Hypertension is related with many other cardiovascular and cerebrovascular diseases like infarction and strokes. Nowadays this tendency is being changed at last and noise pollution is often considered not only as harmful as air pollution but sometimes even more. European and North American countries have taken a number of measures to reduce noise level in big cities. Examples of popular measures include replacement of older paved roads with smoother asphalt, better management of traffic flows and reducing speed limits to 30 km. per hour, using less-noisy models of transport, like electric vehicles, cycling and walking.

 

KEYWORDS: Noise; Pollution; Health; Traffic; Aviation; Vehicle; Electric Car; Cycling; Walking

INTRODUCTION

Noise pollution is a constantly growing problem in all big cities of the world. Many people may not be aware of its adverse impacts on their health. Noise pollution is a major problem both for human health and the environment [1,2]. Long-term exposure to noise pollution can induce variety of adverse health effects like increasing annoyance, sleep disturbance, negative effects on cardiovascular and metabolic system, as well as cognitive impairment in children. Millions of people in big cities suffer from chronic high annoyance and sleep disturbance. It is estimated that school children suffer reading impairment as a result of aircraft noise. Despite the fact that noise pollution is one of the major public health problems in most big cities of the world there was a tendency of underestimating it making accent mostly on-air pollution [3].

World Health Organization (WHO) guidelines for community noise recommends less than 30 A-weighted decibels dB(A) in bedroom during night for good quality sleep and less than 35 dB dB(A) in classrooms to allow good teaching and learning conditions. The WHO guidelines for night noise recommend less than 40 dB (A) 0f annual average (L night) outside of bedrooms to prevent adverse health effects from night noise.

According to European Union (EU) publication:

• about 40% of the population in EU countries is exposed to road traffic noise at levels exceeding 55 dB (A)
• 20% is exposed to levels exceeding 65 dB (A) during daytime and
• more than 30 % is exposed to levels exceeding 55 dB (A) at night

Some groups of people are more vulnerable to noise. For example, children spending more time in bed than adults are more exposed to night noise. Chronically ill and elderly people are more sensitive to disturbance. Shift workers are at increased risk because their sleep structure is under stress. Nuisance at night can lead to increased visits in medical clinics and extra spending on sleeping pills that effects family’s budgets and countries’ health expenditure [4,5].

FACTS AND ANALYSIS

Adverse effect of noise is defined as a change in the morphology and physiology of an organism that results in impairment of functional capacity. This definition includes any temporary or long-term lowering of the physical, psychological or social functioning of humans or human organs. The health significance of noise pollution is given according to the specific effects: Noise-induced hearing impairment, Cardiovascular and physiological effects, Mental health effects, Sleep disturbance and Vulnerable groups.

Noise-Induced Hearing Impairment

The International Organization for Standardization (ISO 1999) standard 1999 gives a method for calculation noise-induced hearing impairment in populations exposed to all types of noise (continu-ous, intermittent, impulsive) during working hours. Noise exposure is characterized by LAeq over 8 hours (LAeq, 8h). In the standard, the relationships between Laeq, 8h and noise-induced hearing impairment are given for frequencies of 500-6000Hz and for exposure time of up to 40 years. These relations show that noise-induced hearing impairment occurs predominantly in the high-frequency range of 3000-6000Hz, the effect being largest at 4000Hz [6,7].

Hearing impairment in young adults and children were assessed by Laeq on 24h time basis [7-9]. It includes pop music in discotheques and rock-music concerts [8]. Pop music through headphones [10,11], music played by brass bands and symphony orchestras [11,12]. There is literature showing hearing impairment in people exposed to specific types of non-occupational noise. These noises originate from shooting, motorcycling, using noisy toys by children, fireworks’ noise [13,14].

In Europe environmental noise causes burden that is second in magnitude to that from air pollution. At least 113million people are suffered from traffic-related noise above 55dB Lden that costs the EU about E57.1 billion a year. Additionally, 22 million Europeans are exposed to railway noise, 4 million to aircraft and about 1 million to industrial noise. All these exposures to noise pollution cause about 1.6 million of life lost annually, about 12000 premature deaths and 48000 cases of ischemic heart diseases. About22 million people suffer from chronic high annoyance and 6.5 million from sleep disturbance [15-17].

Cardiovascular and Physiological Effects

Laboratory studies of workers exposed to occupational noise and noisy streets, indicate that noise can have temporary as well as, permanent impacts on physiological functions in people. Acute noise exposures activate autonomic and hormonal systems, leading to temporary changes such as hyper- tension and ischemic heart diseases associated with long-term exposure to high sound pressure levels [7,11,18]. The magnitude and duration of the effects are determined in part by individual characteristics, lifestyle behaviors and environmental conditions. Sounds also evoke reflex responses, particularly when they are unfamiliar and have a sudden onset. The most occupational and community noise studies have been focused on the possibility that noise may be a risk factor for cardiovascular disease. Studies in occupational settings showed that workers exposed to high levels of industrial noise for many years at their working places have increased blood pressure and risk for hypertension, compared to workers of control areas [19,20]. Cardiovascular adverse effects are associated to long-term exposure of LAeq, 24h. values in the range of 65-70 dB or more, for both air and road-traffic noise.

Mental Health Effects

Environment noise accelerates and intensifies development of adverse effects on mental health by variety of symptoms, including anxiety, emotional stress, nervous complains, nausea, headaches, changes in mood, increase in social conflicts, psychiatric disorders as neurosis, psychosis and hysteria [21-32]. Noise adversely effects cognitive performance. In children environmental noise impairs a number of cognitive and motivational parameters [20,22]. Two types of memory deficits were identified under experimental noise exposure: incidental memory and memory for materials that observer was not explicitly instructed to focus on during learning period. Schoolchildren in vicinity of Los Angeles airport were found to be deficient in proofreading and persistence with challenging puzzles [20]. It has been documented following exposure to aircraft noise that in workers exposed to occupational noise it adversely effects cognitive task performance. In children too environmental noise impairs a number of cognitive and motivational parameters in children too [21-24].

Sleep Disturbance

Annoyance in populations exposed to environmental noise varies not only with the acoustical characteristics of the noise, but also with many non-acoustical factors of social, psychological, or economic nature [17,7]. These factors include fear associated with the noise source, conviction that the noise could be reduced by third parties, individual noise sensitivity, the degree to which an individual feels able to control the noise.

At nights environmental noise starting at Lnight levels below 40 dB, can cause negative effects on sleep such as body movements, awakenings, sleep disturbance, as well as effects on the cardiovascular system that becomes apparent above 55dB [24-27]. It especially concerns vulnerable groups such as children, chronically ill and elderly people. All these impacts contribute to a range of health effects, including mortality. During the COVID-19 pandemic European cities experienced sufficient reduction in noise pollution due to reduced road traffic movement.

The WHO recommends reduction of road traffic noise levels to 53dB during daytime (Lden) and 45dB during the night (Lnight). Though, the Environment Noise Directive (END) sets mandatory reporting for noise exposure at 55dB Lden and 50 dB Lnight [26-28]. It means that we don’t yet have accurate understanding of exact number of people exposed to harmful noise levels as defined by the WHO [5,6].

Vulnerable Groups

Vulnerable groups of people include people with decreased abilities like: people with particular diseases and medical problems; blind people or having hearing impairment; babies and small children; elderly and old-aged people. These people are less able to cope with impairments of noise pollution and are at greater risk to harmful effects. People with impaired hearing are most effected to speech intelligibility. From 40 years aged people demonstrate difficulties to understand spoken messages. Therefore, majority of this population can be belonged to vulnerable group of people. Children are also included in vulnerable group of noise exposure [29]. So, monitoring is necessary to organize at schools and kindergartens to protect children from noise effects. Specific regulations and recommendations should be taken into account according to types of effects for children like, communication, recreation, listening to loud music through headphones, music festivals, motorcycling, etc.

CONCLUSIONS

Our cities have already witnessed welcome period of unusual quiet during confinement periods due to Covid-19 pandemic, but noise pollution is rising again and, in some cases, even more than precrisis levels. It is clear that we cannot live without sound or noise and reducing noise pollution to zero level is unrealistic. However, we must work to make sure that noise be reduced to less harmful levels to environment and human health. Examples of measures include: installing road and rail noise barriers; optimizing aircraft movements around airports and urban planning measures. But the most effective actions to reduce exposure can be reduction of noise at source, namely by reducing number of vehicles, introducing quieter tires for road vehicles and laying quieter road surfaces. Anyway, it is unlikely that noise pollution will decrease significantly in near future and that transport demand is expected to increase. Air traffic noise is also predicted to increase along with city inhabitants. Effective measures against this situation can be raising awareness and changing people’s behavior by using less-noise models of transport, such as electric vehicles, cycling and walking. Zero emission buses must be welcomed in big cities as well, as refuse collection trucks and municipal vans. Required infrastructure of safe cycling must be constructed in cities for safe cycling and available public bike fleet. Such types of transport as motorcycles and scooters must be banned in big cities because they produce the most terrible and loud noise that adversely impacts on citizens. Municipalities and mayors of big cities must organize so-called quiet city areas, like commodity parks and other green spaces, where people can go to escape city noise.

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Effect of Qishan Formula Granules on Interventing Obesity Intestinal Microflora and Immune-Inflammatory by Wei Yan in Open Access Journal of Biogeneric Science and Research

Effect of Qishan Formula Granules on Interventing Obesity Intestinal Microflora and Immune-Inflammatory by Wei Yan in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Objective: To investigate the effects of Qishan Formula Granule on Simple Obesity and Intestinal Microflora-Inflammatory Immune Pathway. Methods: Eighty patients with simple obesity in our hospital were randomly divided into two groups: traditional Chinese medicine group and placebo group. The Chinese medicine group was treated with lifestyle intervention + Qishan formula granule, while the placebo group was treated with lifestyle intervention + placebo. The therapeutic effect, biochemical indexes, clinical symptoms, the number and composition of bacteria, the proportion of Th17/Treg cells in serum and inflammatory factors were measured before and after treatment. Results: After treatment, the total effective rate of simple obesity patients in Chinese medicine group was significantly higher than that in placebo group. (P ＜05). Compared with the placebo group after treatment, the biochemical indexes and clinical symptoms of the Chinese medicine group improved significantly after treatment. Further tests showed that Qishan Formula Granule could significantly improve the intestinal bacterial abundance, species and quantity of simple obesity patients. The levels of IL-17, TNF-alpha, Th17/Treg and LPS in patients with simple obesity in traditional Chinese medicine group were significantly lower than those in placebo group before and after treatment (P ＜ 0.05). Conclusion: Qishan Formula Granule can alleviate clinical symptoms of simple obesity and improve treatment efficiency through intestinal flora-inflammatory immune pathway.

KEYWORDS: Qishan formula granule; Obesity; Intestinal flora; Immune inflammatory; Th17/Treg

In recent years, with the change of people's lifestyle, the incidence of obesity has increased rapidly. For the chronic metabolic disorders celected to obesity and overweight, the prevalence of diseases such as diabetes and cardiovascular and cerebrovascular diseases has increased year by year [1]. Obesity cannot only lead to diabetes or high incidence of cardiovascular and cerebrovascular events, but also closely relate to cancer, depression, asthma, apnea syndrome, infertility, osteoarthropathy, fatty liver and many other diseases [2-5]. Therefore, it has become a serious impact on people's health, it’s urgent to find reasonable and effective intervention measures. At present, the main drugs of weight loss treatment include non-central drugs, central drugs and hypoglycemic drugs, which have many problems such as low effective response rate, large side effects and weight rebound after stopping [6]. The combination of diet and exercise is often difficult to adhere to for a long time, and compliance is poor [7]. Seeking effective drugs or methods to treat simple obesity has become an important research hotspot in recent years.

It is believed that intestinal flora plays an important role in the regulation of immune inflammation and glycolipid metabolism [8,9]. Studies have shown that there is chronic low-level inflammation in obese people, and chronic low-level inflammation caused by obesity may promote the occurrence development of metabolic disorders [10]. At the same time, it has been found that the disorder of intestinal flora and its metabolites in obesity patients and the obvious imbalance of proportion can affect the formation and differentiation of immune cells such as Th17 cells and Treg cells, thus leading to chronic low-level immune inflammation and obesity [11-13]. At present, a number of studies have shown that traditional Chinese medicine has an important effect on intestinal flora, berberine, Gegenqinlian decoction, tonifying traditional Chinese medicine and so on have a certain degree of adjustment of bacterial dysbiosis [14-15]. Qishan formula granules from Gegenqinlian modification, is a national famous old Chinese medicine experience prescription. The results of the previous study showed that Qishan formula has the effect of reducing blood sugar, improving insulin resistance and reducing body weight. However, the mechanism is not clear, and the simple obesity population has not been studied. Therefore, this study explores the efficacy of Qishan Formula Granule in the treatment of simple obesity and its effect on intestinal flora immune inflammatory pathway, in order to provide reference for traditional Chinese medicine in the treatment of obesity.

INFORMATION AND METHODOLOGY

General Information

In this study, A randomized (randomized digital approach), double-blind（The subjects, researchers, surveyors or data analysts did not know the treatment allocation, placebo-controlled, prospective study approach was selected for simple obese patients through health check-ups, community population screening, and outpatient visits. All patients were treated with lifestyle intervention（In a low sugar diet, 200-350g of main food should be eaten every day, and the ratio of carbohydrate to total calories should be 50% - 65%. Low fat diet, fat intake within 50g, about 30% of the total calories. Protein balance, about 15% of the total heat. Encourage the intake of foods rich in dietary fiber and vitamins. The daily total heat is controlled within 100kj / kg. Adhere to moderate intensity aerobic exercise, i.e., heart rate + 170 age after exercise, at least 3-5 days a week. It lasts for half a year; those with diabetes were treated with glizat sustained-release tablets; and those with hypertension were treated with amlodipine. The study included 80 patients who still met the following criteria after the 1-month elution period. a random number table was established using excel software. the standard 80 patients were randomly averaged into two groups: the traditional medicine group (40) and the placebo group (40). In the group of traditional Chinese medicine,14 cases were male and 26 cases were female; the age was 25-50 years, the average age was 38.74±10.23 years; and the average course of disease was 6.63±3.55 years. in the placebo group,16 men and 24 women; age 25-50 years, mean age 39.61±9.83 years; and mean course of disease 6.17±3.82 years.

Inclusion and Exclusion Criteria

Inclusion Criteria

(1)Patients with simple obesity (male waist ≥90 cm, female ≥85 cm, and BMI≥25 kg/m2) in accordance with the 2011 edition of the Expert Consensus on the Prevention and Control of Adult Obesity in China;(2) age greater than 25 years of age less than 70 years of age;(3) classification of TCM syndrome differentiation as obesity-wet-heat accumulation of spleen syndrome ：The body is fat（25kg/m2≤BMI≤28kg/m2：+1score, 28kg/m2≤BMI≤30kg/m2：+2scores, 30kg/m2≤BMI：+3scores,）; the abdomen is full(+1score); the food is little and tired(+1score); the head is heavy as wrap(+1score),The loose stool is not good(+1score); the urine color is yellow(+1score); and the whole body is hot and humid jaundice(+1score);The tongue is fat(+2scores); with yellow and greasy fur(+2scores);and smooth veins(+2scores);(4) discontinuation of drugs affecting weight for 4 weeks; (5) signing of informed consent.

Exclusion Criteria

(1)Weight gain due to drugs, endocrine diseases or other diseases;(2) severe liver and kidney dysfunction or other severe primary diseases;(3) history of acute cardiovascular and cerebrovascular events or myocardial infarction within 6 months;(4) stress state or secondary blood glucose elevation or secondary hypertension;(5) weight-loss surgery within one year;(6) severe dyslipidemia;(7) unwillingness of cooperators (who cannot cooperate with dietary control or do not use drugs as prescribed);(8) mental illness, tumor patients;(9) women with or breast-feeding, and women with planned or unplanned contraception;(10) possible allergy to gestational drugs;(11) patients with diabetes who have received medication.

Treatment

(1) The Chinese medicine group was given lifestyle intervention + qishan formula granules orally, one pack at a time, twice a day. (The formulas are: Pueraria root 15g, Scutellaria baicalensis 10g, Coptis chinensis 10g, Rhubarb 3g, gynostemma pentaphyllum 10g, Shengqi 20g, Huai yam 20g, Atractylodes chinensis 15g, Poria cocos 15g, fried Fructus Aurantii 10g, Raw Hawthorn 10g, Chuanxiong 10g, produced by the preparation room of traditional Chinese medicine in our hospital). (2) The placebo group was given a lifestyle intervention plus a placebo oral dose, twice daily. (The formulas are: starch, pigment and adhesive, which are produced by the traditional Chinese medicine preparation room of our hospital).

Indicator Measurements

Fasting blood glucose (FPG), blood lipids, blood pressure, waist-to-hip ratio, body mass index (BMI), body fat content, tcm symptom score (and other biochemical indicators, clinical symptoms were measured every 4 weeks. HbA1c, fasting insulin (FINS), fecal intestinal flora, proportion of serum th17/treg cells and serum IL-17, TNF-α, liver and kidney function, blood routine, urine routine, electrocardiogram were measured at week 0 and 12.

Determination of Flora Size and Composition

Quantitative intestinal excreta were diluted and inoculated into bs medium (bifidobacterium isolate) anaerobic culture for 48 h, bbe medium (bacillus isolates) anaerobic culture for 24h, lactic acid bacteria selective medium for 24h, enterococcal agar for 24h, fs medium (clostridium isolates) for 72h, kf streptococcus agar (streptococcus isolates) anaerobic culture for 24 h, and iridium agar for 24h. After the growth of the colony, the desired target bacteria were identified by colony morphology, Gram staining and biochemical reaction. On a variety of different media, the colonies were identified, and the number of each bacteria was compared with the reference value, and the B/E value was calculated to evaluate the number and composition of intestinal flora in patients with simple obesity after oral intervention of Qishan without sugar.

PCR-DGGE Analysis Intestinal Flora Composition

Fecal specimen collection and DNA extraction: The collection of feces of simple obese patients by aseptic method was about 1 g in 2 mL EP tube, and the stool genomic DNA was extracted according to the instructions of the DNA extraction kit.pcr: the v3 section of bacterial 16srdna was amplified by universal primers. the amplification conditions were 94°c for 3 min predenaturation,94° c for 1 min denaturation,55°c for 1 min annealing,72°c for 1 min extension, a total of 36 cycles,72°c for 10 min extension, and 4°c preservation.PCR products were detected by 2% agarose gel electrophoresis and stored at -20°C.dgge: the pcr product was separated on 8% polyacrylamide glue, the gel was stained by gelred after the end, the gs-800 grayscale scanner was imaged, and the correlation analysis of dgge molecular fingerprint was performed by biomerics software.

Quantitative Quantitative PCR Analysis of Intestinal Microflora

Fecal specimen collection and DNA extraction: The collection of feces of simple obese patients by aseptic method was about 1 g in 2 mL EP tube, and the stool genomic DNA was extracted according to the instructions of the DNA extraction kit. PCR primer design: according to Bifidobacterium, Lactobacillus, Escherichia coli, Bacillus, Clostridium, Streptococcus 16SrDNA gene sequence, the corresponding bacterial PCR primer was designed, and the specificity of the corresponding bacterial sequence was compared in the BLAST gene bank. Preparation of the standard curve: the PCR products of each bacteria in the control group were purified according to the instructions of the DNA purification kit, and the absorbance (A value) and concentration of the purified product were determined, and the copy number of each standard product 1μl was converted to be used to make the standard curve.

Detection of Biochemical Indexes

Blood sugar, blood lipids and other biochemical indicators were determined by the Olimpas 2000 large automatic biochemical instrument. serum insulin, hba1c was determined by our advia centur®xp fully automated chemiluminescence immunoanalyzer. Serum LPS was detected by ELISA. Methods for the determination of intestinal flora and SCFAs:2g of fresh feces of patients were frozen at -20°C refrigerator with a toilet provided by the Institute of Microbiology of Zhejiang Province (containing stabilizer), and the Institute was commissioned to test it. Body fat content was determined by the department's own body fat tester.HOMA-IR is calculated by formula HOMA-IR = FPG × FINS /22.5, HOMA-IS is calculated by formula HOMA-IS =1/HOMA-IR=22.5/ FPG × FINS.

Anges Of Th17/Treg Cells Before and After Intervention

The peripheral blood of the two groups of patients was collected, standing for 1 h,2000 rpm,4°c, centrifuged for 10 min, collected and packed into supernatant, and stored at -20°c when not detected in time. the content of serum il-17, tnf- α was determined by double antibody sandwich enzyme-linked immunosorbent assay (elisa), and the specific operation was carried out strictly according to the instructions of elisa kit. cd3-pecy7 and cd4-pe 0.5μg each, after oscillating and mixing evenly, incubated at room temperature for 30 min;300 g centrifuged for 5 min. after washing with cold pbs,1 ml of diluted fixed, membrane-penetrating agent was added. after reaction for 50 min, the concentration of th17 and treg cells was determined by flow cytometry.

Safety Evaluation and Adverse Reaction Management

If there is an alt increase during medication, the principle of adjusting the drug dose or interrupting treatment is:1 If the alt increase is within 2 times the normal value, continue to observe. If ALT rises at 2-3 times the normal level and is taken in half, continue to observe if ALT continues to rise or remains between 80-120 U.L-1 and interrupt treatment. 3 If ALT rises above 3 times the normal value, stop the drug. After the withdrawal of drugs return to normal can continue to use, and strengthen the treatment of liver protection and follow-up. If leukopenia occurs during medication, the principles for adjusting the drug dose or interrupting treatment are as follows:1 If leukopenia is not lower than 3.0 x 109·L-1, continue to take medication to observe. If the white blood cell drops between (2.0 and 3.0) ×109·L-1, observe in half. Most patients can return to normal during continued medication. If the review of leukocytes is still below 3.0 x 109·L-1, the treatment is interrupted. 3 If leukopenia falls below 2.0 x 109·L-1, interrupt treatment.

CRITERIA FOR EVALUATION OF SYNDROME EFFICACY

Clinical recovery: TCM clinical symptoms, signs disappear or basically disappear, syndrome score reduction ≥90% and weight lost by ≥ 15%. Remarkable effect: the clinical symptoms and signs of TCM were obviously improved, and the score of syndromes was reduced by more than 70% and weight lost by ≥ 10%. Effective: TCM clinical symptoms, signs are improved, syndrome score reduction≥30% and weight lost by ≥ 5%. Invalid: TCM clinical symptoms, signs are not significantly improved, or even aggravated, syndrome score reduction <30% or weight lost by<5%. Total effective = (clinical recovery + significant + effective)/ total number *100%.

Statistical Analysis

Statistical software SPSS 17.0 is used to compare and analyze the indexes in this paper. The measurement data are expressed in form, and the measurement data are normally distributed, which meet the t-test standard.T-test to compare the counting data with xs test comparison; the count data are compared by Χ2 test; when p < 0.05, the statistics have significant differences.

Estimation of Sample Size

Estimation of sample size: according to the estimation method of sample size in clinical experimental research, the sample size of two sample mean comparison is estimated. Check the "sample size table required for two sample mean comparison". According to the bilateral α = 0.05, the test efficiency (1- β) = 0.9, μ 0.05 = 1.96, μ 0.1 = 1.28, according to the previous research experience, σ is the estimated value of the overall standard deviation of two samples = 16, δ is both samples. The difference of number = 3.0, and the result is n = 34. Considering the loss rate of sample 15%, 40 cases in the experimental group and 40 cases in the control group were preliminarily determined.

RESULTS

The rate of abscission and baseline were compared between the two groups. In the placebo group, 40 cases were enrolled, 2 cases were dropped, 38 cases were observed, and the drop rate was 5%. In the treatment group of traditional Chinese medicine, 40 cases were enrolled, 3 cases fell off, 37 cases were observed, the rate of falling off was 7.5%. There were 12 diabetic patients in placebo group, 15 hypertensive patients, 13 diabetic patients and 14 hypertensive patients in traditional Chinese medicine treatment group. There was no significant difference between the two groups in the proportion of diabetic and hypertensive patients. The age gender, baseline FPG, total cholesterol, triglyceride, LDL, BMI, body fat content, HbA1c, fins, waist to hip ratio, TCM syndrome score and the number of specific intestinal flora were comparable.

Groups Comparison of Clinical Effect of Simple Obesity Patients After Treatment

Compared with the placebo group after treatment, the total effective rate of simple obese patients in the traditional chinese medicine group was significantly increased after treatment (81.1% vs 50.0 %), and there was a significant difference in comparison (p <0.05). the clinical efficacy of the two groups was compared in table 1. Further observation found that the two groups of patients did not have liver function, renal function, abnormal white blood cell level and other adverse reactions Table 1.

Two Groups Comparison of Biochemical Indexes of Simple Obesity Patients Before and After Treatment

Compared with the previous treatment, the indexes of the patients with simple obesity in placebo group did not change significantly after treatment, and there was no significant statistical difference (P >0.05). The scores of FPG, total cholesterol, triglyceride, low-density lipoprotein, BMI, body fat, HbA1c, FINS, waist-to-hip ratio and TCM syndromes were significantly lower in patients with simple obesity than before and after treatment group of placebos, whereas HDL was significantly higher than that before and after treatment placebo group, there was a significant difference in comparison (P <0.05); the comparison of biochemical indexes before and after treatment in the two groups was shown in Table 2.

Groups Patients with simple obesity before and after treatment Comparison of intestinal flora

The colony numbers of Bifidobacterium, Bacillus fragilis, Lactobacillus, Enterococcus and Escherichia coli in the placebo group were not significantly different after treatment compared with that before and after treatment (P >0.05). The colony numbers of Bifidobacterium and Bifidobacterium in the traditional Chinese medicine group were significantly higher than those in the comfort group before and after treatment (P <0.05). A similar result was found for the detection of bacterial copy number of each stool by real-time fluorescence quantitative PCR, and the real-time fluorescence quantitative PCR is shown in Table 4.

Two Groups Comparison of Inflammatory Indexes in Simple Obesity Patients Before and After Treatment

Compared with pre-treatment, the inflammatory indexes of patients with simple obesity in placebo group did not change significantly after treatment (P >0.05)The levels of IL-17, TNF-α and Th17/Treg were significantly lower in patients with simple obesity than those before and after treatment placebo group, there was a significant difference in comparison (P <0.05); the comparison of biochemical indexes before and after treatment in the two groups was shown in Table 5.according to the relationship between th17/treg level and normal range after treatment of qishan formula granules, it was divided into normal group (th17/treg level was within normal range) and high level group (th17/treg level was higher than normal range). Further statistics found that the total amount of intestinal flora after treatment in the normal group was significantly higher than that in the high-level group (P <0.05, Fig.1) Table 3.

Table 1:  Comparison of clinical efficacy between the two groups

Remark: *: P <0.05 compared to placebo group (Chi square test)

Table 2: Comparison of biochemical indexes between the two groups before and after treatment

Remark: *: P <0.05 Compared with the group before treatment;

#: P <0.05; comparision of difference between the two groups before and after treatent;

Table 3: Comparison of intestinal flora between the two groups before and after treatment

 

Remark: *: P <0.05 Compared with the group before treatment;

#: P <0.05; comparision of difference between the two groups before and after treatment;

Table 4: Real-time fluorescence quantification of bacterial copies of PCR feces

Remark: *: P <0.05 Compared with the group before treatment;

#: P <0.05; comparision of difference between the two groups before and after treatment;

Table 5: Comparison of inflammatory indexes between the two groups before and after treatment

Remark: *: P <0.05 Compared with the group before treatment;

#: P <0.05; comparision of difference between the two groups before and after treatent;

DISCUSSION

In recent years, with the rapid development of today's society, people's life style and diet, nutrition structure has undergone great changes, so the incidence of obesity remains high, and the incidence of diabetes, cardio-cerebrovascular diseases and other diseases caused by obesity is increasing year by year. Several studies have shown that Qishan formula granules play an important role in reducing body weight. Therefore, this study discussed the effect of Qishan formula granule on simple obesity and further discussed its mechanism.

This study found that the total effective rate of simple obesity patients was significantly increased after the intervention of qishan formula granules. at the same time, the intervention of qishan formula granules could improve the clinical symptoms and biochemical indexes such as blood sugar and blood lipids in simple obesity patients. The application of Qishan formula granules is beneficial to the treatment of simple obese patients. The theory of traditional Chinese medicine believes that obesity is due to dietary fat, inactivity,dysfunction of spleen in transportation, accumulation of phlegm and dampness cream. Body diseases characterized by obesity and fatigue. Its most common symptom is damp-heat accumulation spleen syndrome [16,17]. Qishan formula granules from Gegenqinlian decoction and six gentleman decoctions reduced. Raw astragalus, huai yam, poria qi invigorating spleen, Scutellaria baicalensis, Coptis chinensis Qingzhongjiao dampness and heat, rhubarb, gynostemma pentaphyllum to remove dampness, Atractylodes aromatization and dampness, Fructus Aurantiii, Hawthorn Qi digestion, phlegm elimination, Pueraria, Chuanxiong heat Qingjin Qi Huoxue. Thus, it has the effect of invigorating qi and invigorating spleen, clearing away heat and removing dampness and removing turbidity. It can make temper health transport and water Tianjin four cloth, phlegm turbidity inside the heat clear and fat in the full elimination. The purpose of removing Glycyrrhiza in the original prescription of Gegen Qinlian decoction is to prevent the rise of blood sugar and the storage of water and sodium.Therefore, the application of Qishan formula granules can significantly improve the total effective rate of patients and significantly improve clinical symptoms, blood sugar, blood lipids and other biochemical indicators. However, the mechanism of cell biology and molecular biology has not been elucidated Table 5.

Several studies have pointed out that differences in the composition of the intestinal flora are one of the most important causes of obesity, and their mechanisms mainly involve activating inflammatory responses, promoting energy absorption and regulating intestinal permeability [18,19] Studies have shown that obese patients are often accompanied by inflammatory signaling pathway activation, immune cell infiltration and other pathological changes [20]. therefore, stopping from the intestinal flora-inflammatory immune pathway will be helpful to elucidate the mechanism of qishan formula granules to improve simple obesity. this study examined the number and composition of intestinal flora and found that the colony numbers lactic acid bacteria, bifidobacterium and bacteroides were significantly higher in patients with simple obesity than in the placebo group before and after treatment after treatment after treatment with qishan formula granules. The results showed that Qishan formula could significantly affect the intestinal flora of simple obese patients. He Xuyun and other studies have found that Astragalus polysaccharide, the main ingredient of Astragalus membranaceus, can significantly inhibit the formation of obesity in mice and significantly restore intestinal flora disorders [21]. At the same time, several studies have pointed out that Radix Puerariae, Scutellariae, Coptis, Huai yam, Ligusticum chuanxiong, Poria cocos and Astragalus membranaceus It can affect the composition and richness of intestinal flora [22-25]. thus further confirming the effect of Qishan formula granules on intestinal flora.Intestinal flora plays an important regulatory role in the balance of immune cells. Fang Qian et al found a linear positive correlation between Bifidobacterium/ Escherichia coli ratio and Treg/Th17 in children with asthmatic bronchitis [26]. At the same time, numerous studies have found that berberine regulates the intestinal flora and the balance of Th17/Treg cells in rats, while the disruption of the balance between pro-inflammatory Th17 cells and inhibitory Treg cells is a key factor in many immune and metabolic diseases [27-29]. Therefore, the effect of Qishan formula granules on inflammatory cells and inflammatory factors was further examined. the results showed that il-17, tnf-α, th17/treg and levels were significantly reduced in patients with simple obesity after intervention of qishan formula granules, indicating that qishan formula granules could affect the inflammatory response in patients with simple obesity. further exploring the relationship between th17/treg levels and intestinal flora found that the total amount of intestinal flora in patients with th17/treg levels in the normal range was significantly higher than that of patients with th17/treg levels than normal, indicating a association between intestinal flora and treg/th17 values in patients with simple obesity. In summary, Qishan formula granules can improve the symptoms of obesity by increasing the richness and diversity of intestinal flora in simple obese patients and inhibiting the inflammatory response.

To sum up, this study found that Qishan formula granules can alleviate the clinical symptoms of simple obesity and improve the treatment efficiency through the intestinal flora-inflammatory immune pathway. Qishan formula granules can regulate the proportion of Th17, Treg cells and the secretion level of inflammatory factors by influencing the composition and richness of intestinal flora, so as to reshape the body shape and improve the biochemical index, and then achieve the purpose of treating simple obesity. However, there are still some shortcomings in this study, and it is necessary to further explore the main components of its efficacy and how the intestinal flora affects the inflammatory response.

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