Research progress on the general gout formula in Zhu Danxi

Research progress on the general gout formula in Zhu Danxi

Xiao Zhan said, Luo Chenggui, Yin Haibo

The upper, middle and lower general gout formula is the famous formula for the treatment of gout in Zhu Danxi, because of its rich medicinal composition and comprehensive disease mechanism, so it has a good clinical effect on a variety of diseases. Through the literature search, it was found that there was no systematic review of the upper, middle and lower general gout prescriptions. In order to make this party better used in clinical practice, this paper will sort out and discuss the historical evolution, group analysis, clinical research, experimental research and other aspects of the general gout side from the upper, middle and lower levels, review its modern research progress, and provide theoretical and literature reference for further in-depth research of this side.

1 Overview of the upper, middle, and lower general gout parties

Zhu Danxi was the first doctor to systematically discuss gout after Tao Hongjing first proposed the term "gout", "gout" disease is mainly joint pain, combined with numbness, swelling, etc., equivalent to a variety of arthritis diseases [1-2]. Zhu Danxi's many books mention the main recipe for the treatment of gout, and the "Golden Hook Xuan" is named "Upper, Middle and Lower Gout Formula", which is composed of 13 herbs of ginger-made Southern Star, Swill Immersion Technique, Wine Stir-fried Yellow Cedar, Sichuan Root, Bai Zhi, Stir-fried Divine Comedy, Peach Kernel, Wine Mixed With Wei Lingxian, Qiang Huo, Self-Defense, Guizhi, Wine Washed Safflower, gentian Herb. Later generations of physicians greatly respected the fang, until the Ming Dynasty physician Wu Kun said in the "Medical Examination" that "this set of medicine for treating gout is also." And renamed as "Danxi lord upper middle and lower universal gout party", the first use of the word "universal", and later to the Qing Dynasty Wang Ang's "Soup Song Recipe" followed the name of "upper, middle and lower universal gout party", the book was published in large quantities, so that this party name was widely circulated.

The general gout formula in the upper, middle and lower levels is an important prescription for Zhu Danxi to treat gout, and the discussion is found in many of his works, "Danxi Heart Method", "Danxi Hand Mirror", "Golden Hook Xuan", and "Danxi Zhifa Heart Essentials" The four books have conducted in-depth discussions on the principle of making the formula, addition and subtraction changes. Zhu Danxi believes that gout disease is caused by wind, cold, dampness, heat, qi, phlegm, stasis, weakness, alcohol poison, the pathogenesis is the invasion of wind, cold, wet and other external evils, blood heat, damp heat, phlegm turbidity, wine poison connotations, resulting in meridian blood veins blocked and unable to make pain and become gout. According to this, the upper, middle and lower general gout prescriptions are established. Use Bai Zhi, Qiang Huo, Gui Zhi to dispel wind and cold, Cang Shu and Huang Cedar for the two mysterious scattering, Wu use gentian grass, self-defense to clear the damp heat, peach kernel, safflower to activate blood stasis, Jiang Nanxing to dissolve phlegm, Sichuan Root to activate blood and qi, the whole party to dispel wind and cold, dampness and heat removal, gasification phlegm, blood stasis.

2 Clinical study of the upper, middle and lower general gout prescription

2.1 Gout

Gout refers to a disease in which the human body's blood uric acid exceeds its saturation in the blood or tissue fluid, locally forms sodium urate crystals in the joints and deposits them to induce local inflammatory responses and tissue destruction. In the acute attack, the main thing is to control the symptoms of acute arthritis, and to control blood uric acid and prevent acute attacks in the intermittent and chronic phases[3]. Gu Lingli et al. [4] 120 patients with gout were randomly divided into a control group and a treatment group of 60 cases each, the control group was given Western medicine often punol 0.2g/d, and the treatment group was treated only with the addition and subtraction of the chinese medicine upper and lower gout formula, and the total effective rate of the treatment group was 94.3% after 4 weeks, and the control group was 55%, and the treatment group was better than the control group in terms of improvement in blood uric acid value, and the difference was statistically significant.

Shen Ping et al. [5] 68 patients with gout were randomly divided into 34 cases in the control group and 34 cases in the treatment group, and the control group was given celecoxib capsules 100mg/d, and the treatment group was treated with this side, and the levels of erythrocyte sedimentation rate and blood uric acid in the treatment group after the trial were significantly better than those in the control group, and the pain relief onset time and longer analgesic duration in the treatment group were significantly different. Luo Zhengkai et al. [6] Randomly divided 70 patients with acute gout arthritis into a control group and a treatment group of 35 patients, respectively, diclofenac sodium sustained-release capsules of 50mg/d, and the treatment group added the upper, middle and lower universal gout formula, and the joint swelling and pain scores of the two groups after treatment were lower than before treatment, and the joint swelling pain scores and disease courses of the treatment group were smaller than those of the control group, and the difference was statistically significant. Wang Xiaoyue et al. [7] 63 patients with gouty arthritis after joint dissection were randomly divided into 28 cases in the control group and 35 cases in the treatment group, and the control group took benzbromalong tablets 50mg 1 time/day and etocoxib tablets 120mg 1 time/day, and the treatment group only took the addition and subtraction of the treatment, and the level of erythrocyte sediment rate, blood uric acid and C-reactive protein indicators in the two groups after treatment was significantly reduced, and the treatment group was better than the control group ( <0.01）。 Both groups used visual analog scoring (VAS) to evaluate joint pain scores and the joint Lysholm scoring system to evaluate joint function, and both scores improved, and the treatment group was more significant. Zhong Jiaoying [8] Used the upper, middle and lower general gout prescription to treat 60 patients with sputum wet stasis gout nephropathy, the study showed that this formula can effectively improve clinical symptoms and signs, and can significantly reduce the blood uric acid, blood creatinine, urea nitrogen, total cholesterol, triglycerides, 24h urine protein quantification in patients, and the difference is statistically significant. The "Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout in China (2019)" lists benzbrommarone in uric acid-reducing drugs and allopurinol in uric acid-inhibiting drugs as first-line drugs for the treatment of uric acid in gout patients[3], and clinical studies have shown that the upper, middle and lower general gout prescriptions have advantages in lowering uric acid compared with these two drugs, indicating that this formula can play a role in inhibiting uric acid production and promoting uric acid excretion, which can highlight its obvious advantages in lowering uric acid. In the acute phase of gout, the Guidelines recommend NSAIDs as first-line medications[3], and the Eicoxib, diclofenac sodium, celecoxib and upper, middle, and lower general gout prescriptions in NSAIDs are used in clinical studies, and studies have shown that these drugs are superior to these drugs. And in addition to symptom relief and lowering indicators, this formula can also reduce kidney damage, delay the decline of kidney function, and protect kidney function.

2.2 Rheumatoid arthritis

In addition to gouty arthritis, the upper, middle and lower general gout prescription also has a good clinical effect on other diseases with arthritis. Li Xing et al. [10] randomly divided 72 patients with rheumatoid arthritis into 36 cases in the experimental group and 36 cases in the control group. Both groups of patients were given methotrexate 10mg/week treatment, the experimental group added upper, middle and lower universal gout prescription treatment, after 12 weeks showed that the total effective rate of the experimental group was 79.4%, better than the total effective rate of the control group of 56.3%, the difference was statistically significant, the duration of morning stiffness, joint tenderness, grip strength, joint function, daily living ability evaluation and erythrocyte sedimentation rate, C-reactive protein test group was better than the control group. It shows that the upper, middle and lower general gout prescription combined with methotrexate in the treatment of rheumatoid arthritis is better than that of single methotrexate therapy. Yao Xinyan et al. [11] 64 patients with rheumatoid arthritis with damp heat barrier and cold and heat mixed evidence were randomly divided into 32 cases in the treatment group and 32 cases in the control group, and the control group was given methotrexate combined with sulfasalazine, and the treatment group added upper, middle and lower general gout formulas on this basis. The symptom improvement and blood rheological index improvement of the treatment group were better than the control group, and the total effective rate of the treatment group was 93.75%, which was better than that of the control group by 71.88%. A number of clinical research data show that the treatment of rheumatoid arthritis can improve symptoms and reduce indicators.

2.3 Other rheumatic immune diseases

The upper, middle and lower general gout formula also has significant efficacy in the treatment of other rheumatic immune diseases. Cao Hongxin used this formula to treat systemic lupus erythematosus, dry syndrome and other evidence that the effect of damp and heat stasis is remarkable, and believes that the diseases caused by wind, cold, humidity, heat, phlegm, and blood stasis have the opportunity to use this method by seizing the core disease mechanism [12]. Gao Yuzhong [13] The use of this formula to treat rheumatic polymyalgia and articular psoriasis is satisfied with the efficacy of damp heat. Yuan Deli et al. [14] used this formula to treat myofasciitis, Zhang Caiping [15] used this formula to add or subtract to treat the hot and toxic palm toe pustules, and Liu Yupu [16] used this method to treat erythema nodosum, and achieved good efficacy.

2.4 Non-rheumatic immune diseases

Due to the wide coverage of the upper, middle and lower general gout prescription drugs, it can also treat more non-rheumatic immune diseases. Zhu Jinzhong [17] believes that this party can remove the evil of rheumatic fever phlegm stasis, smooth the rise and fall of the three-coke machine, and use this method to treat a variety of diseases, such as cerebral hemorrhage with diabetic acidosis coma, globulbar calcification of forgetfulness, carbon monoxide poisoning after dementia, cerebral thrombosis of hemiplegia aphasia, chronic erysipelas, skin tuberculosis and other evidence of wind cold and closed depression, phlegm heat connotation, qi stagnation and blood stasis. Feng Yufei et al. [18] followed Zhu Jinzhong's treatment method and used this formula to treat patients with cerebral hemorrhage who were internal witnesses of external wind chill and phlegm fever. Xu Hao [19] Retrospectively analyzed the pain symptom relief of 63 patients with hemorrhoidal surgery after using the upper, middle and lower general gout prescription, and this study confirmed that the upper, middle and lower general gout soup has a significant effect on the refractory pain after hemorrhoid surgery and can effectively relieve pain. Zhang Yonglan et al. [20] use this formula to treat painful diseases such as frozen shoulder and sciatica. In summary, the upper, middle and lower general gout formula has a multi-target effect, so it should firmly grasp the core pathogenesis of its treatment when using it to expand the scope of application.

3 Basic research on the upper, middle and lower general gout side

3.1 Lowering uric acid

Elevated hematuric uric acid levels are the root cause of the occurrence and development of hyperuricemia and gout and their associated comorbidities, so controlling hematuria can significantly reduce the frequency of gout attacks, prevent tophi formation, prevent bone destruction, reduce the risk of death and improve the quality of life of patients. Is key to preventing gout and its associated comorbidities [3]. Basic research has also shown the advantages of the upper, middle and lower general gout formula in lowering blood uric acid. Li Xin et al. [21] Using our own intervention in the high uric acid rat model, the uric acid levels in each group were significantly lower than those in the model group, and the uric acid lowering effect was better than that of the allopurinol group, and the serum urea nitrogen (BUN) and serum creatinine (Cre) levels in the Chinese medicine group were significantly lower than those in the model group. Experimental results show that the upper, middle and lower general gout decoction has a significant anti-hyperuricemia effect, which can significantly reduce the level of blood uric acid and reduce uric acid production, and also has a protective effect on the kidneys. Liu Ying[22] studied the basis of the mechanism of action of this formula to reduce uric acid, indicating that the mechanism of action of this formula to lower blood uric acid may be achieved by increasing the urinase activity of liver tissue and reducing the activity of xanthine oxidase in liver tissue. Wang Lili[23] studies have also shown that this formula can inhibit the activity of xanthine oxidase in liver tissue, reduce the production of blood uric acid, and may inhibit the reabsorption of uric acid by downregulating the expression of renal tissue URAT1, thereby reducing blood uric acid levels. Multiple experiments have verified from different angles that the upper, middle and lower general gout formula can reduce uric acid levels, and the mechanism of action may be related to increasing the activity of liver tissue uridase, inhibiting xanthine oxidase activity, and down-regulating the expression of URAT1 in kidney tissue.

3.2 Anti-inflammatory

The pathological mechanism of gout is very complex, not only has a high level of uric acid involved, but also has a certain degree of inflammatory response, so the treatment of gout anti-inflammatory is also very important, many basic studies have explored the anti-inflammatory mechanism of the upper, middle and lower general gout formula. Li Xin et al. [24] demonstrated that this formula can reduce interleukin-1 (IL-1), IL-6, tumor necrosis factor - (TNF-) levels, Zhou Liya et al. [25] studies have shown that this formula can reduce peripheral blood Th17 cell levels and serum IL-17 levels. Han Yusheng [26-27] studies have shown that this formula can reduce the level of serum IL-12 and IL-23, significantly reduce the content of prostaglandin E2 (PGE 2) in inflammatory tissues, and downregulate the expression of vascular cell adhesion molecule-1 (VCAM-1) protein in synovial tissue. Park Yu-sung et al. [28] verified that this formula can also inhibit the expression of COX-2 protein in synovial tissue. Li Baolong et al. [29] verified that this party can significantly reduce the level of white blood cell number, TNF-, PGE 2, IL-1, IL-8 in rabbit joint fluid, thereby inhibiting inflammatory cell chemotactin, activation, inhibition of inflammatory factors and cytokine synthesis and release. Xin Li et al. [30] studies have shown that this party may downregulate the expression of toll-like receptor 4 (TLR4) and nuclear transcription factor-B (NF-B) proteins in rat model synovial tissues. Zhou Liya et al. [31] studies have shown that ben can downregulate the expression of TLR4 and MYD88 proteins.

Studies have shown that the upper, middle and lower general gout decoction has a good anti-inflammatory analgesic effect on acute gouty joint inflammation caused by sodium urate, and its mechanism of action may be related to the reduction of the inflammatory factors IL-1, IL-1, IL-8, IL-6, IL-12, IL-17, IL-23, TNF- levels, lower Th17 cells, inhibition of COX-2, down-regulation of PGE2, VCAM-1, TLR4, NF-B, MYD88 and other signaling pathways.

3.3 Other mechanism studies

Some teams have also explored other mechanisms in addition to antiuric acid and anti-inflammatory. Duan Shuxiang et al. [32] Conducted research from the perspective of antioxidants, verified that this formula can significantly reduce the level of malondialdehyde, the end product of lipid peroxidation in the synovial membrane of gout rats, improve the activity of the body's antioxidant dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and can block the lipid peroxidation chain reaction to exert antioxidant effects, thereby treating gout arthritis. In terms of the treatment mechanism of other diseases, Fei Hongxin et al. [33] showed that this formula has inhibitory effects on the key proteins Shh, Smo, Ptch1 and Gli1 of the hedgehog signaling pathway of pancreatic cancer BxPC-3 cells. Zhang Xiaojie et al. [34-35] found that the treatment of Alzheimer's disease had a certain efficacy, and did relevant basic studies to prove that the party may reduce the blood-brain barrier permeability and hippocampal amyloid 1-40 (A 1-40) by down-regulating the hippocampal late glycosylated end-product receptor receptor (RAGE) and upregulating hippocampal low-density lipoprotein receptor-related protein 1 (LRP1). At the same time, it was verified that this formula may improve the hippocampal learning and memory ability and hippocampal morphological structure of Alzheimer's disease mice by inhibiting the hippocampus-amyloid precursor protein (APP), hippocampal amyloid 1-42 (A 1-42), IL-1 and TNF-.

4 Conclusion

The upper, middle and lower general gout prescriptions have outstanding advantages in the treatment of gout and other diseases because of their rigorous compatibility, rich composition, multi-target treatment and high safety. According to the search for the relevant literature of clinical research and basic research in recent years, modern physicians have grasped the core disease mechanism of this party in the guiding principle of dialectical basis, further expanded the scope of application, and achieved certain research results in basic research. In the collation, the author also found that there are still some problems that need to be solved urgently: (1) The upper, middle and lower general gout side has more research on rheumatic immune diseases, and some clinical studies have shown that there are also good effects on other systemic diseases such as encephalopathy and digestive system diseases, but there are relatively few clinical studies in other systemic diseases. (2) The rationality of the clinical study design of the upper, middle and lower general gout prescription is relatively lacking, and the number of cases is small, and the lack of high-quality large-sample randomized double-blind controlled studies provides more powerful evidence-based medical evidence for the determination of efficacy. (3) Basic research focuses on uric acid lowering and anti-inflammatory, of which there are relatively few research on anti-inflammatory signaling pathways, and other basic research is relatively weak.