Pharmaceutical composition containing curdione

Abstract

The invention discloses a pharmaceutical composition containing curdione. The pharmaceutical composition is characterized in that it is found that curdione can improve the cardiac function of myocardial ischemia / reperfusion model rats. The combined use of curdione and stigma croci glucose ester E has a synergistic effect, and when the curdione and the stigma croci glucose ester E are taken together with trehalose, the effect is the best. Moreover, the invention accidentally finds that after the curdione is compounded with the crocus sativus glucose ester E and the trehalose, not only can the injury caused by oxidative stress in reperfusion therapy be effectively improved, but also the injury of the curdione to the liver can be reduced.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition containing turmeric dione, and more particularly to a pharmaceutical composition containing turmeric dione that has a protective effect against myocardial ischemia injury. It belongs to the field of biomedicine. Background Technology

[0002] Ischemic heart disease (IHD) is a common cardiovascular disease that seriously threatens human health. In my country, the incidence and mortality rates of IHD have been rising year by year over the past 20 years, with a trend of higher rates in rural areas than in urban areas. IHD medical resources are extremely expensive, placing a heavy burden on patients, families, and society, undoubtedly posing a serious challenge to public health and healthcare. Currently, the fundamental solution to IHD is to restore coronary blood flow in a timely manner; however, the accompanying ischemia-reperfusion injury is unavoidable, often worsening the patient's condition in clinical practice. Developing effective drugs to improve the damage caused by oxidative stress during reperfusion therapy has profound guiding significance for the treatment of myocardial ischemia-reperfusion injury.

[0003] Curcuma species, traditional Chinese medicinal herbs, are widely used in the clinical treatment of various diseases due to their diverse pharmacological activities. Curdione (Cd) is a sesquiterpene compound in the volatile oils of Curcuma plants. Although reports on Cd have increased in recent years, the main research focus has been limited to tumor-related diseases, anti-inflammatory factors, and its effects on platelet aggregation. Therefore, in-depth exploration of Cd's antioxidant activity is essential. On the one hand, elucidating its mechanism of action is a key question that needs to be answered before Cd can be applied clinically, providing a theoretical basis for drug administration during myocardial ischemia-reperfusion and enriching clinical treatment options.

[0004] The present invention aims to provide a pharmaceutical composition containing turmeric dione, and particularly relates to a pharmaceutical composition containing turmeric dione that has a protective effect against myocardial ischemia injury. Summary of the Invention

[0005] The purpose of this invention is to provide a pharmaceutical composition containing turmeric dione, and more particularly to a pharmaceutical composition containing turmeric dione that has a protective effect against myocardial ischemia injury.

[0006] Curcuma longa, a traditional Chinese medicinal herb, is widely used in the clinical treatment of various diseases due to its diverse pharmacological activities. Curcuma dione, one of the main active ingredients in Curcuma zedoaria, has effects such as promoting qi circulation, stopping bleeding, relieving pain, and reducing inflammation. It is also found to have significant effects on tumor-related diseases, anti-inflammatory factors, and platelet aggregation.

[0007] An unexpected discovery in this invention is that curcuminone also has antioxidant effects and may play an auxiliary protective role against myocardial ischemia injury through the Nrf2 / HO-1 pathway.

[0008] Saffron, also known as Tibetan saffron or crocus, is made from the dried stigmas of the saffron plant (Crassula ovata), belonging to the genus Crocus in the family Oleaceae. It is a valuable traditional Chinese medicine used both as food and medicine, possessing properties of promoting blood circulation, removing blood stasis, warming the meridians, cooling the blood, detoxifying, relieving depression, and calming the mind. A new compound has been isolated from saffron: (2E,4E)-2-methyl-6-hydroxy-2,4-heptadienoic acid-1-O-β-D-binan glucopyranose ester, named Saffron Glucopyranose E, with the structure shown below:

[0009]

[0010] The technical problem to be solved by this invention can be achieved through the following technical solutions.

[0011] Curcuma longa, a traditional Chinese medicinal herb, is widely used in the clinical treatment of various diseases due to its diverse pharmacological activities. Curcuma dione, one of the main active ingredients in Curcuma zedoaria, has effects such as promoting qi circulation, stopping bleeding, relieving pain, and reducing inflammation. It is also found to have significant effects on tumor-related diseases, anti-inflammatory factors, and platelet aggregation.

[0012] Saffron, also known as Tibetan saffron or crocus, is made from the dried stigmas of the saffron plant (Crassula ovata), belonging to the genus Crocus in the family Oleaceae. It is a valuable traditional Chinese medicine used both as food and medicine, possessing properties of promoting blood circulation, removing blood stasis, warming the meridians, cooling the blood, detoxifying, relieving depression, and calming the mind. A new compound has been isolated from saffron: (2E,4E)-2-methyl-6-hydroxy-2,4-heptadienoic acid-1-O-β-D-binan glucopyranose ester, named Saffron Glucopyranose E, with the structure shown below:

[0013]

[0014] A pharmaceutical composition having the following content:

[0015]

[0016] After mixing the above substances evenly, the desired result is obtained.

[0017] Advantages of this invention:

[0018] This invention discloses a pharmaceutical composition containing turmeric dione, which has been found to improve cardiac function in rats with a myocardial ischemia / reperfusion model. The combined use of turmeric dione and saffron glucose ester E has a synergistic effect, with the best results observed when turmeric dione and saffron glucose ester E are administered in combination with trehalose. Furthermore, this invention unexpectedly discovered that the combination of turmeric dione, saffron glucose ester E, and trehalose not only effectively improves the damage caused by oxidative stress during reperfusion therapy but also reduces the liver damage caused by turmeric dione. Detailed Implementation

[0019] The embodiments of the present invention are described in detail below. These embodiments are only used to explain the present invention and should not be construed as limiting the present invention.

[0020] Specific embodiments of the present invention are described below.

[0021] Example 1

[0022] Curcuma longa, a traditional Chinese medicinal herb, is widely used in the clinical treatment of various diseases due to its diverse pharmacological activities. Curcuma dione, one of the main active ingredients in Curcuma zedoaria, has effects such as promoting qi circulation, stopping bleeding, relieving pain, and reducing inflammation. It is also found to have significant effects on tumor-related diseases, anti-inflammatory factors, and platelet aggregation.

[0023] Saffron, also known as Tibetan saffron or crocus, is made from the dried stigmas of the saffron plant (Crassula ovata), belonging to the genus Crocus in the family Oleaceae. It is a valuable traditional Chinese medicine used both as food and medicine, possessing properties of promoting blood circulation, removing blood stasis, warming the meridians, cooling the blood, detoxifying, relieving depression, and calming the mind. A new compound has been isolated from saffron: (2E,4E)-2-methyl-6-hydroxy-2,4-heptadienoic acid-1-O-β-D-binan glucopyranose ester, named Saffron Glucopyranose E, with the structure shown below:

[0024]

[0025] A pharmaceutical composition having the following content:

[0026]

[0027] After mixing the above substances evenly, the desired result is obtained.

[0028] Example 2:

[0029] A pharmaceutical composition having the following content:

[0030]

[0031] After mixing the above substances evenly, the desired result is obtained.

[0032] Example 3:

[0033] A drug that contains only curcuminidine.

[0034] Example 4:

[0035] A drug that contains only saffron glucose ester E.

[0036] Example 5:

[0037] A pharmaceutical composition having the following content:

[0038]

[0039] After mixing the above substances evenly, the desired result is obtained.

[0040] Example 6:

[0041] Crocin is an extract of saffron, also known as crocin. Current research has shown that crocin has a certain protective effect against various diseases.

[0042] A pharmaceutical composition having the following content:

[0043]

[0044]

[0045] After mixing the above substances evenly, the desired result is obtained.

[0046] Example 7:

[0047] A pharmaceutical composition having the following content:

[0048]

[0049] After mixing the above substances evenly, the desired result is obtained.

[0050] Example 8

[0051] Methods for establishing a rat model of myocardial ischemia / reperfusion: Ten-week-old SD rats, weighing 200-220g, were selected. There were no statistically significant differences in sex and weight among the groups, with five rats in each group. The SD rats were anesthetized intraperitoneally with 10% chloral hydrate (3ml / 100g), fixed in a supine position, and a ventilator endotracheal tube was inserted. The skin was incised on the left side of the sternum to expose the heart. The pericardium was carefully dissected with forceps, and the left anterior descending coronary artery was located between the conus medullaris and the left atrial appendage. A 6-0 silk suture was passed through the myocardium below the left anterior descending coronary artery to a depth of approximately 3mm, avoiding penetration of the left ventricle. A soft tube was placed between the suture and the heart, and the left anterior descending coronary artery was ligated to induce myocardial ischemia. When ischemia occurred, the apex of the heart darkened and then turned white, indicating a successful ischemia model. After 30 minutes of ischemia, the ligation was loosened, the soft tube was removed, and myocardial blood supply was restored. Reperfusion was then performed for 2 hours.

[0052] The laboratory animals were grouped and treated in the following manner:

[0053] Sham surgery group: only open-chest surgery was performed, but ischemia was not treated;

[0054] Model group: The model group was given an equal volume of normal saline by gavage once a day for 7 consecutive days. The ischemia-reperfusion injury model was established 30 minutes after the last gavage.

[0055] Positive control group: Trimetazidine hydrochloride 5 mg / kg, administered by gavage once a day for 14 consecutive days. The ischemia-reperfusion injury model was established 30 minutes after the last gavage.

[0056] Example 1 group: The drug composition of Example 1 was administered at a dose of 30 mg / kg once daily by gavage for 14 consecutive days, after which an ischemia-reperfusion injury model was established.

[0057] Example 2 group: The method was the same as in Example 1 group, but the drug composition of Example 2 was administered by gavage at a dose of 30 mg / kg;

[0058] Example 3 group: The method is the same as that of Example 1 group, but Curcuma dione of Example 3 is administered by gavage at a dose of 20 mg / kg;

[0059] Example 4 group: The method was the same as that of Example 1 group, but the saffron glucose ester E of Example 4 was administered by gavage at a dose of 2 mg / kg;

[0060] Example 5 group: The method is the same as that of Example 1 group, and the drug composition of Example 5 is administered by gavage at a dose of 22 mg / kg;

[0061] Example 6 group: The method is the same as that of Example 1 group, and the drug composition of Example 6 is administered by gavage at a dose of 30 mg / kg.

[0062] Example 7 group: The method is the same as that of Example 1 group, and the drug composition of Example 7 is administered by gavage at a dose of 30 mg / kg.

[0063] Two hours after perfusion, left ventricular ejection fraction (LVEF) was determined by echocardiography, and other left ventricular diameters were measured. Then, anesthetized rats were cannulated into the left ventricle, and left ventricular end-diastolic pressure (LVEDP) was measured. Statistical analysis was performed using SPSS 17.0 software. Normality tests and homogeneity of variance analyses were conducted. One-way ANOVA was used to compare means among multiple groups. Quantitative data were expressed as mean ± standard deviation (mean ± SD), and P < 0.05 was considered statistically significant. The results are shown in Table 1 below:

[0064] Table 1. Cardiac function assessment for each group

[0065] Group LVEF (%) LVEDP (mmHg) Sham surgery group 75.20±8.16 6.59±1.59 Model group 42.69±3.40 17.26±2.02 Positive control group 68.96±9.05 10.39±1.09 Example 1 Group 67.98 ± 8.15 1，2 ]] 9.83 ± 1.21 1，2 ]] Example 2 group 65.76 ± 7.26 1，2 ]] 10.27 ± 1.17 1，2 ]] Example 3 Group 50.42 ± 6.24 1，2，3 ]] 14.20 ± 1.52 1，2，3 ]] Example 4 group 43.25 ± 3.78 1，3 ]] 17.10 ± 1.98 1，3 ]] Example 5 group 55.23 ± 5.52 1，2，3 ]] 12.52 ± 1.88 1，2，3 ]] Example 6 group 50.82 ± 6.76 1，2，3 ]] 14.10 ± 2.10 1，2，3 ]] Example 7 group 56.23 ± 4.85 1，2，3 ]] 13.06 ± 1.80 1，2，3 ]]

[0066] Note: 1: P<0.05 (compared with sham-operated group); 2: P<0.05 (compared with model group); 3: P<0.05 (compared with positive control).

[0067] Table 1 shows that turmeric alone can increase ejection fraction, decrease left ventricular end-diastolic pressure, and improve cardiac function in rats with myocardial ischemia / reperfusion model, while saffron glucose ester E alone cannot improve cardiac function and has no statistical significance. The combined use of turmeric and saffron glucose ester E significantly improved cardiac function (comparison between Example 5 and Examples 3 and 4, P < 0.05, statistically significant), indicating a synergistic effect. When turmeric and saffron glucose ester E were taken with trehalose, cardiac function remained normal, showing the highest improvement, close to the positive control group, indicating a very good effect. However, when turmeric and saffron glucose ester E were taken with sucrose, there was no significant improvement in their synergistic effect, suggesting that trehalose may increase the absorption rate of turmeric and saffron glucose ester E in the gastrointestinal tract.

[0068] Example 9

[0069] Assessment of the degree of injury in the myocardial ischemia-reperfusion model: Two hours after perfusion, approximately 3 ml of femoral artery blood was collected. Serum was separated using a high-speed centrifuge at 3000 rpm and stored in an ultra-low temperature freezer (-70°C) for later use. Inflammatory factors (IL-1β, IL-6) and oxidative stress markers (MDA) were measured using a double-antibody sandwich ELISA method. Statistical methods were the same as in Example 8. The results are shown in the following two tables:

[0070] Table 2 Assessment of the degree of injury in each group of myocardial ischemia-reperfusion models

[0071] Group IL-1β (pg / mL) IL-6 (pg / mL) MDA (umol / L) Sham surgery group 2.36±0.22 3.62±0.28 0.45±0.09 Model group 9.08±0.50 12.50±1.06 1.66±0.12 Positive control group 5.04±0.45 6.44±0.71 0.72±0.13 Example 1 Group 5.66 ± 0.52 1，2 ]] 6.76 ± 0.79 1，2 ]] 0.59 ± 0.09 1，2 ]] Example 2 group 5.98 ± 0.48 1，2 ]] 6.99 ± 0.86 1，2 ]] 0.62 ± 0.07 1，2 ]] Example 3 Group 8.12 ± 0.74 1，2，3 ]] 10.98 ± 0.92 1，2，3 ]] 1.25 ± 0.10 1，2，3 ]] Example 4 group 9.00 ± 0.69 1，3 ]] 12.44 ± 1.08 1，3 ]] 1.62 ± 0.15 1，3 ]] Example 5 group 7.36 ± 0.80 1，2，3 ]] 9.12 ± 0.81 1，2，3 ]] 1.05 ± 0.11 1，2，3 ]] Example 6 group 8.00 ± 0.96 1，2，3 ]] 10.11 ± 0.97 1，2，3 ]] 1.20 ± 0.09 1，2，3 ]] Example 7 group 7.26 ± 0.75 1，2，3 ]] 9.01 ± 0.75 1，2，3 ]] 1.00 ± 0.14 1，2，3 ]]

[0072] Note: 1: P<0.05 (compared with sham-operated group); 2: P<0.05 (compared with model group); 3: P<0.05 (compared with positive control).

[0073] Table 2 shows that turmeric alone can reduce inflammatory factors Il-1β and IL-6 to a certain extent, and reduce the oxidative stress factor MDA, thereby reducing myocardial ischemia-reperfusion injury; while saffron glucose ester E alone has no significant protective effect and is not statistically significant. The combined use of turmeric and saffron glucose ester E can enhance the protective effect on cardiac function, indicating a synergistic effect. When turmeric and saffron glucose ester E are taken with trehalose, the protective effect is strongest, with MDA even exceeding that of the positive control group and approaching that of the sham-operated group, indicating a very good effect. However, when turmeric and saffron glucose ester E are taken with sucrose, there is no significant increase in the synergistic effect, which is considered to be related to trehalose increasing the absorption and conversion rate of turmeric and saffron glucose ester E in the gastrointestinal tract.

[0074] Example 10

[0075] Detection of proteins related to the myocardial ischemia-reperfusion injury signaling pathway: Rats were sacrificed, and myocardial tissue was harvested along a fixed section. The expression of Nrf2 and HO-1 proteins in the myocardial tissue was detected according to the basic immunohistochemical procedure. The results were analyzed using ImageJ software, and the statistical methods were the same as in Example 8. The results are shown in Table 3 below:

[0076] Table 3. Expression of Nrf2 and HO-1 proteins in myocardial tissue of each group.

[0077]

[0078]

[0079] Note: 1: P<0.05 (compared with sham-operated group); 2: P<0.05 (compared with model group); 3: P<0.05 (compared with positive control).

[0080] Table 3 shows that curcuminone alone can increase Nrf2 and HO-1 protein levels; while saffron glucose ester E alone has no significant effect and is not statistically significant. The combined use of curcuminone and saffron glucose ester E can increase Nrf2 and HO-1 protein levels, indicating a synergistic effect. The most significant increase is observed when curcuminone and saffron glucose ester E are taken with trehalose, suggesting a synergistic effect among curcuminone, saffron glucose ester E, and trehalose, which improves oxidative stress-induced damage during myocardial reperfusion therapy through the Nrf2 and HO-1 signaling pathways.

[0081] Example 11

[0082] The ALT and AST activities in the serum of each group in Example 8 were measured using an ALT kit and an AST kit. The results are shown in Table 4.

[0083] Table 4 Liver function tests for each group

[0084] Group ALT(U / L) AST(U / L) Sham surgery group 10.15±1.09 12.28±1.75 Model group 12.02±0.72 13.11±1.29 Positive control group 12.43±1.24 12.85±1.40 Example 1 Group 19.26 ± 4.29 1，2，3 ]] 20.96 ± 3.95 1，2，3 ]] Example 2 group 18.59 ± 3.32 1，2，3 ]] 18.62 ± 2.99 1，2，3 ]] Example 3 Group 33.26 ± 4.44 1，2，3 ]]> 31.48 ± 3.69 1，2，3 ]] Example 4 group 14.26±1.58 13.26±1.51 Example 5 group 28.25 ± 2.26 1，2，3 ]] 29.26 ± 1.99 1，2，3 ]] Example 6 group <![CDATA[33.15±3.05 1，2，3 ]]> <![CDATA[30.48±3.29 1，2，3 ]]> Example 7 group <![CDATA[28.59±3.04 1，2，3 ]]> <![CDATA[29.24±1.78 1，2，3 ]]>

[0085] Note: 1: P<0.05 (compared with sham-operated group); 2: P<0.05 (compared with model group); 3: P<0.05 (compared with positive control).

[0086] Curcuma zedoaria and safflower, as components of traditional Chinese medicine, have certain toxicity to the liver, spleen, and kidneys. Existing studies have found that the use of Curcuma zedoaria extract in patients with liver damage can worsen their liver injury. This invention found that Curcuma zedoaria alone significantly increased liver enzymes compared to the sham-operated group; however, saffron glucose ester E alone had no effect and was not statistically significant. The combined use of curcuma dione and saffron glucose ester E reduced ALT and AST, indicating a synergistic effect. The effect was most pronounced when curcuma dione and saffron glucose ester E were taken with trehalose. It is believed that curcuma dione, saffron glucose ester E, and trehalose have a synergistic effect, which can reduce the liver damage caused by Curcuma zedoaria.

[0087] It should be noted that the above description is only a preferred embodiment of the present invention. Any changes made in accordance with the concept of the present invention that do not exceed the spirit covered by the specification should be within the scope of the present invention.

[0088] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0089] Although embodiments of the invention have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A pharmaceutical composition containing curcuminidine, characterized in that, The content is as follows:

2. The pharmaceutical composition containing turmeric dione according to claim 1, characterized in that... The structure of saffron glucose ester E is as follows:

3. The pharmaceutical composition containing curcuminone according to claim 1 or 2, characterized in that: The pharmaceutical composition containing turmeric dione is made into tablets.

4. The pharmaceutical composition containing curcuminone according to claim 1 or 2, characterized in that: The pharmaceutical composition containing turmeric dione is made into capsules.

5. The use of the pharmaceutical composition containing turmeric dione according to any one of claims 1-4 in the preparation of a pharmaceutical product.

Images