Application of a large bupleurum decoction combined with crocin in the preparation of aecopd drugs

Abstract

The application relates to the technical field of combined medicines, and discloses application of a Dachaihu decoction combined with crocin in preparation of AECOPD medicines, which comprises the Dachaihu decoction and crocin, and the mass ratio of the Dachaihu decoction to the crocin is 284:5; wherein the mass of the Dachaihu decoction is recorded according to the mass of medicinal materials. The Dachaihu decoction has the advantages of small side effect and high safety in treatment of AECOPD, and the crocin can improve the lung function of patients in the acute exacerbation period of chronic obstructive pulmonary disease by down-regulating the expression of NLRP3, inhibit oxidation stress and inflammatory reaction, and inhibit alveolar epithelial cell apoptosis. The Dachaihu decoction is creatively combined with the crocin, and the combination can play a synergistic role in treatment of the acute exacerbation period of chronic obstructive pulmonary disease, so that the Dachaihu decoction combined with the crocin has an application prospect of development into a medicine for treatment of the acute exacerbation period of chronic obstructive pulmonary disease.

Description

Technical Field

[0001] This invention relates to the field of combined medicine technology, and in particular to the application of Da Chai Hu Tang combined with crocin in the preparation of AECOPD drugs. Background Technology

[0002] Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) refers to an acute onset process characterized by a severe and rapid worsening of symptoms in patients with chronic obstructive pulmonary disease. This involves an acute deterioration beyond the normal range of respiratory symptoms, necessitating changes in treatment plans. The main manifestations include severe dyspnea, increased cough, and purulent sputum with increased sputum volume, thus requiring additional treatment methods beyond conventional approaches.

[0003] Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are an independent risk factor for death in the vast majority of COPD patients, and the level of prevention and treatment directly affects patient survival. Currently, Western medicine often treats AECOPD with bronchodilators, corticosteroids, and antibiotics, along with assisted ventilation. However, there is a lack of specific Western medicines to control its progression. While these drugs can alleviate clinical symptoms and improve lung function to some extent, long-term use of corticosteroids and antibiotics easily leads to drug resistance, increases the risk of superinfections and other related complications, and results in poor long-term prognosis for some patients. Therefore, many medical professionals combine Western medicine with traditional Chinese medicine in their treatment regimens.

[0004] Da Chai Hu Tang is a traditional Chinese medicine formula originating from Zhang Zhongjing's *Treatise on Febrile and Miscellaneous Diseases*. It consists of Bupleurum, Scutellaria baicalensis, Paeonia lactiflora, Pinellia ternata, Citrus aurantium, Rheum palmatum, Ziziphus jujuba, and Zingiber officinale. It is a formula that addresses both the exterior and interior, harmonizing the Shao Yang and purging internal heat accumulation. It is primarily used to treat combined Shao Yang and Yang Ming syndromes, characterized by alternating chills and fever, fullness and discomfort in the chest and hypochondrium, persistent vomiting, mild irritability, epigastric fullness and hardness, or epigastric pain, constipation, or diarrhea with fever, a yellow tongue coating, and a wiry, rapid, and forceful pulse. Clinically, it is often used to treat acute pancreatitis, acute cholecystitis, cholelithiasis, and gastric and duodenal ulcers belonging to the combined Shao Yang and Yang Ming syndromes.

[0005] Crocin is derived from the fruits of Gardenia jasminoides (a plant in the Rubiaceae family), saffron (a plant in the Iridaceae family), and the stigmas of other plants in the same genus. It has immunomodulatory effects. Clinically, saffron is used to treat various chronic diseases in humans. Through its effects of promoting blood circulation, removing blood stasis, antibacterial and anti-inflammatory properties, it enhances the body's endurance and lymphocyte proliferation response, thereby improving the body's cellular and humoral immunity, and playing a role in regulating the body's Qi circulation and balancing Yin and Yang.

[0006] Currently, there are no studies, either domestic or international, that have shown that Da Chai Hu Tang and crocin have a synergistic effect in preventing and treating acute exacerbations of chronic obstructive pulmonary disease (COPD), nor are there any reports of using Da Chai Hu Tang and crocin together to treat acute exacerbations of COPD. Summary of the Invention

[0007] To overcome the problems existing in the prior art, this invention proposes the application of Da Chai Hu Tang combined with crocin in the preparation of AECOPD drugs, and its detailed technical solution is as follows:

[0008] An application of Da Chai Hu Tang combined with crocin in the preparation of AECOPD drugs, comprising Da Chai Hu Tang and crocin, wherein the mass ratio of Da Chai Hu Tang to crocin is 284:5; wherein the mass of Da Chai Hu Tang is based on the mass of the medicinal materials.

[0009] Furthermore, it contains 30g of Bupleurum chinense, 15g of Scutellaria baicalensis, 20g of Pinellia ternata, 20g of Citrus aurantium, 15g of Paeonia lactiflora, 20g of Zingiber officinale, 12g of Ziziphus jujuba, 10g of Rheum palmatum, and 2.5g of Crocin.

[0010] A drug for treating acute exacerbations of chronic obstructive pulmonary disease, comprising Da Chai Hu Tang (a traditional Chinese medicine formula), crocin, and pharmaceutically acceptable excipients; wherein the mass ratio of Da Chai Hu Tang to crocin is 284:5; wherein the mass of Da Chai Hu Tang is based on the mass of the medicinal materials.

[0011] Furthermore, the dosage form of the drug is capsules, pills, tablets, granules, or injections.

[0012] According to any of the above embodiments, the present invention has at least the following beneficial effects: Da Chai Hu Tang has the advantages of few side effects and high safety in the treatment of AECOPD, while crocin can improve lung function in patients with acute exacerbations of chronic obstructive pulmonary disease by downregulating NLRP3 expression, inhibiting oxidative stress and inflammatory response, and inhibiting alveolar epithelial cell apoptosis. The present invention creatively combines Da Chai Hu Tang and crocin, which can exert a synergistic therapeutic effect on acute exacerbations of chronic obstructive pulmonary disease. Therefore, Da Chai Hu Tang combined with crocin has the potential to be developed into a drug for the treatment of acute exacerbations of chronic obstructive pulmonary disease. Detailed Implementation

[0013] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention are described clearly and completely below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0014] In this invention, the mass ratio of Da Chai Hu Tang to the crocin can be 250-300:5, preferably 284:5.

[0015] Experimental method: Six-week-old SPF grade rats were selected and housed in an animal room at 20-25 degrees Celsius, humidity of 30-50%, with 12 hours of light and 12 hours of darkness, and free access to food and water.

[0016] An acute exacerbation model of chronic obstructive pulmonary disease (COPD) was established. From day 1 to 28 (except days 7, 14, and 28), rats were placed in a glass fumigation chamber and fumigated for 30 minutes with 5% smoke concentration. The rats were then transferred to a normal environment. On days 7, 14, and 28, 0.2 ml of 1 g / L endotoxin was instilled into the trachea. From days 29 to 32, 0.3 ml of 2.4*10... 9 CFU / ml Staphylococcus aureus solution, twice daily.

[0017] Crocin was obtained from a directly purchased crocin solution. The Da Chai Hu Tang sample consisted of 30g Bupleurum, 15g Scutellaria baicalensis, 20g Pinellia ternata, 20g Citrus aurantium, 15g Paeonia lactiflora, 20g Zingiber officinale, 12g Ziziphus jujuba, and 10g Rheum palmatum. Before decocting, all the herbs except Rheum palmatum were soaked in 6 times their volume of water for 2 hours. The decoction was then prepared twice: the first decoction for 90 minutes and the second for 60 minutes. The decoctions were filtered through gauze while hot. The two decoctions were then mixed and freeze-dried in a vacuum at -80°C to obtain a powder. The powder was reconstituted with double-distilled water to a concentration of 1g / ml (based on the weight of the herbs).

[0018] Forty mice were randomly divided into four groups: a model group, a saffron group, a Da Chai Hu Tang (Major Bupleurum Decoction) group, and a combined treatment group (Da Chai Hu Tang + saffron), with ten mice in each group. The day of grouping was designated D0. Starting from D1, the combined treatment group received Da Chai Hu Tang suspension (2.84 g / kg, based on the weight of the medicinal material) via gavage daily, followed by an intraperitoneal injection of 50 mg / kg saffron solution (based on the weight of saffron). The Da Chai Hu Tang group received Da Chai Hu Tang suspension (2.84 g / kg, based on the weight of the medicinal material) via gavage daily, followed by an intraperitoneal injection of sterile saline 30 minutes later. The saffron group received double-distilled water via gavage daily, followed by an intraperitoneal injection of 50 mg / kg saffron solution (based on the weight of saffron) 30 minutes later. The model group received double-distilled water via gavage daily, followed by an intraperitoneal injection of sterile saline 30 minutes later. The treatment lasted for 21 days.

[0019] Lung function of rats in each group was observed. The ratio of forced expiratory volume in 0.3 seconds (FEV0.3 / FVC), peak expiratory flow (PEF), and minute ventilation (MV) were recorded. The results are shown in Table 1.

[0020]

[0021] Table 1

[0022] The crocin group, Da Chai Hu Tang group, and combined drug administration group were compared with the model group. ** P < 0.01; Compared with the model group, the Da Chai Hu Tang group... * P < 0.05; compared with the crocin group, the combined drug administration group, ## P < 0.01; compared with the Da Chai Hu Tang group, the combined drug administration group, △△ P < 0.01.

[0023] The results show that, compared with the model group, the levels of PEF, MVV, and FEV0.3 / FVC were significantly increased in the saffron group, Da Chai Hu Tang group, and combined drug administration group. Moreover, the values ​​of PEF, MVV, and FEV0.3 / FVC in the combined drug administration group were greater than those in the saffron group and Da Chai Hu Tang group.

[0024] The relative expression of NLRP3 and caspase-1 mRNA in the lung tissue of rats in each group is shown in Table 2.

[0025] Group n NLRP3 / GAPDH caspase-1 / GAPDH Model group 10 3.30±0.17 2.11±0.49 Crocin group 10 2.28±0.24** 1.59±0.23* Da Chai Hu Tang group 10 2.25±0.32** 1.57±0.53* Crocus extract + Da Chai Hu Tang combination 10 1.06±0.27**##△△ 1.01±0.18**#△

[0026] Table 2

[0027] The crocin group, Da Chai Hu Tang group, and combined drug administration group were compared with the model group. ** P < 0.01; the saffron group and the Da Chai Hu Tang group were compared with the model group, * P < 0.05; compared with the crocin group, the combined drug administration group, ## P < 0.01; compared with the Da Chai Hu Tang group, the combined drug administration group, △ P < 0.01.

[0028] It can be seen that, compared with the model group, the levels of NLRP3 and caspase-1 mRNA in the lung tissue of rats in the crocin group, Da Chai Hu Tang group, and combined drug administration group were significantly reduced.

[0029] The relative expression of NLRP3 and caspase-1 proteins in the lung tissue of rats in each group is shown in Table 3.

[0030] Group n NLRP3 / GAPDH caspase-1 / GAPDH Model group 10 2.31±0.08 1.35±0.21 Crocin group 10 0.88±0.36** 0.89±0.05** Da Chai Hu Tang group 10 0.86±0.34** 0.93±0.14** Crocus extract + Da Chai Hu Tang combination 10 0.28±0.45**##△△ 0.32±0.08**##△△

[0031] Table 3

[0032] Among them, the crocin group, the Da Chai Hu Tang group, and the combined drug administration group were compared with the model group. ** P < 0.01; compared with the crocin group, the combined drug administration group, ## P < 0.01; compared with the Da Chai Hu Tang group, the combined drug administration group, △△ P < 0.01.

[0033] It can be seen that, compared with the model group, the NLRP3 and caspase-1 proteins in the lung tissue of rats in the saffron group, Da Chai Hu Tang group, and combined drug administration group were significantly reduced.

[0034] Based on the symptoms and characteristics of AECOPD attacks, it can be categorized under the traditional Chinese medicine (TCM) categories of "asthma" and "pulmonary distension." Clinical treatment has revealed that AECOPD is often induced by external pathogens, presenting as an acute condition with impaired Shaoyang meridian function, disrupted Qi circulation, and impaired blood flow. Pathogenic factors clash with the body's vital energy, accumulating in the hypochondrium, causing lung Qi to rise and intestinal Qi to stagnate, gradually leading to Yangming heat stagnation. Therefore, clinical manifestations often include shortness of breath, cough with copious sputum, chest and hypochondriac distension, dry mouth and bitter taste, alternating chills and fever, dizziness, abdominal distension and constipation, a red tongue with a thick, greasy yellow coating, and in severe cases, petechiae and ecchymosis on the tongue, and purplish-dark lips and nails. Using the Six Channels Differentiation method from the Treatise on Cold Damage, it was identified as a combined Shaoyang and Yangming syndrome. The classic formula Da Chai Hu Tang was applied to harmonize the Shaoyang meridian and promote the descent of Yangming heat stagnation, yielding significant therapeutic effects.

[0035] Crocin can improve lung function in rats with acute exacerbations of chronic obstructive pulmonary disease by downregulating NLRP3 expression, inhibiting oxidative stress and inflammatory response, and suppressing alveolar epithelial cell apoptosis.

[0036] To verify the synergistic effect of Da Chai Hu Tang and crocin, this invention employs the Jin Zhengjun Q-value method, i.e., Q = MAB / (MA + MB - MA * MB), where the numerator represents the "measured combined effect" and the denominator is the "expected combined effect." MA, MB, and MAB represent the inhibition rate of drug A, the effect value of drug B, and the inhibition rate of the two drugs combined at the current dose, respectively. The synergistic effect index Q is defined as follows: when the Q value is less than 0.85, the two drugs are considered to have an antagonistic effect; when the Q value is between 0.85 and 1.15, the two drugs are considered to have an independent, additive effect; when the Q value is greater than 1.15, the two drugs are considered to have a synergistic effect. In this invention, serum IL-1β levels are used to characterize NLRP3 expression, and the results are shown in Table 4.

[0037] Group n IL-1β Decline rate Kim Jong-kyun's Q value Model group 10 2.87 / / Crocin group 10 1.81** 36.9％ / Da Chai Hu Tang group 10 1.76** 38.7％ / Crocus extract + Da Chai Hu Tang combination 10 0.71**##△△ 75.3％ 1.23

[0038] Among them, the crocin group, the Da Chai Hu Tang group, and the combined drug administration group were compared with the model group. ** P < 0.01; compared with the crocin group, the combined drug administration group, ## P < 0.01; compared with the Da Chai Hu Tang group, the combined drug administration group, △△ P < 0.01.

[0039] As shown in Table 4, the combined use of Da Chai Hu Tang and crocin can significantly reduce the serum IL-1β content and inhibit oxidative stress and inflammatory response by downregulating NLRP3 expression. The two have a synergistic effect in treating acute exacerbations of chronic obstructive pulmonary disease.

[0040] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The application of Da Chai Hu Tang combined with crocin in the preparation of AECOPD drugs, characterized in that, The formula contains Da Chai Hu Tang (Major Bupleurum Decoction) and saffron, with a mass ratio of 284:

5. The mass of Da Chai Hu Tang is based on the mass of the medicinal materials. It contains 30g of Bupleurum, 15g of Scutellaria baicalensis, 20g of Pinellia ternata, 20g of Citrus aurantium, 15g of Paeonia lactiflora, 20g of Zingiber officinale, 12g of Ziziphus jujuba, 10g of Rheum palmatum, and 2.5g of saffron.

Images