WO2014106473A1

WO2014106473A1 - Use of glycyrrhetinic acid or glycyrrhizic acid in preparing medicaments for preventing or treating radiation injury of soft tissue

Info

Publication number: WO2014106473A1
Application number: PCT/CN2014/070090
Authority: WO
Inventors: 张纬建; 洪金省; 张亨山; 韩德平; 吕文龙
Original assignee: 厦门鹭佳生物科技有限公司
Priority date: 2013-01-04
Filing date: 2014-01-03
Publication date: 2014-07-10
Also published as: CN103908458A

Abstract

Disclosed is use of glycyrrhetinic acid or glycyrrhizic acid in preventing or treating radiation injury of soft tissue. Therefore, glycyrrhetinic acid or glycyrrhizic acid can be used for preparing medicaments for preventing or treating radiation injury of soft tissue. The medicament prepared from glycyrrhetinic acid or glycyrrhizic acid has advantages of low cost, good curative effect, low toxicity and side effect during administration in long term and so on. Glycyrrhetinic acid or glycyrrhizic acid can also be used for preparing health care products, foods or food additives for preventing or treating radiation injury of soft tissue.

Description

Application of glycyrrhetinic acid and glycyrrhizin in preparing medicine for preventing or treating radioactive soft tissue injury

The invention relates to the field of pharmaceuticals, health products, foods or food additives. In particular, the present invention relates to the use of glycyrrhetinic acid and glycyrrhizic acid for the preparation of a medicament, a health supplement, a food or a food additive for preventing or treating radiation soft tissue damage. Background technique

Clinically, radiation therapy has been one of the main means of cancer treatment. However, almost none of the patients receiving radiation therapy are immune to radiation damage, including soft tissue injuries. Radiation can cause a series of acute and chronic permanent soft tissue reactions and injuries, manifested as reversible acute hair loss, ulcers, dermatitis, pigmentation and irreversible skin atrophy, destruction of sebaceous glands and sweat glands, hair loss after a long time, skin, subcutaneous Soft tissue fibrosis of tissue or muscle, even radioactive necrosis. Radioactive soft tissue fibrosis can directly affect the normal function of tissues and organs, and seriously affect the quality of life of patients. In view of the high incidence of side effects of radioactive soft tissue injury, there have been no effective preventive or therapeutic drugs to date, and radioactive soft tissue damage has become a thorny problem for radiation therapy. Therefore, the present invention prepares a drug, a health care product, a food or a food additive which is urgently needed to effectively prevent or treat radioactive soft tissue damage and which is low in toxicity to the human body.

In addition to the above-mentioned tumor radiotherapy for the near and long-term damage of normal human tissues and organs, the damage of ionizing radiation also includes: (1) clinical diagnosis of X-ray examination of tissue and organs in special populations; (2) direct engagement and exposure to radioactive substances Injury of staff and researchers (including: radiology medical staff, nuclear tests and nuclear power plant staff, etc.); (3) Natural radiation material background damage to the human body (cosmic radiation, background radiation, food and building materials, etc.) (4) The impact of artificial nuclear power plants on the surrounding radiation and the human body; (5) Possible nuclear war and the harm of nuclear terror to the public.

After the Second World War, researchers began looking for low-toxic radiation protectants to protect normal tissues from radiation damage. Studies have found that agents that scavenge free radicals and/or cause hypoxia have radiation protection values, such as amino mercaptans, which produce the highest protection factor. They can protect animals (mainly rodents) from radiation damage if used before radiation exposure [Prasad KN. Handbook of Radiobiology

(Handbook of radiobiology). Second Edition. Boca Raton, FL: CRC Press, 1995]. However, most of these compounds are toxic to humans at radiation protection doses. The development of new radiation protection drugs has been listed as the top priority research project by many countries. In summary, there is an urgent need in the art for drugs, health care products, foods or food additives that are effective in preventing or treating radiation soft tissue damage and are low in toxicity to humans. Summary of the invention

It is an object of the present invention to provide a use of glycyrrhetinic acid or glycyrrhizic acid for the preparation of a medicament, a health care product, a food or a food additive for preventing or treating radiation soft tissue damage.

Another object of the present invention is to provide a use of glycyrrhetinic acid or glycyrrhizic acid for the preparation of ancillary drugs, health care products, foods or food additives for improving the efficacy of radiation therapy. In a first aspect, the present invention provides the use of glycyrrhetinic acid or glycyrrhizic acid for the preparation of a medicament, health care product, food or food additive for preventing or treating radiation soft tissue damage.

In a preferred embodiment, the medicament, health supplement, food or food additive is used in the adjuvant treatment of radiation therapy.

In a preferred embodiment, the radioactive soft tissue injury comprises damage to subcutaneous tissue, muscle or bone caused by radiation.

In a preferred embodiment, the radioactive soft tissue injury comprises damage to acutely radioactive subcutaneous tissue, muscle or bone.

In a further preferred embodiment, the radioactive soft tissue injury comprises acute radiation subcutaneous tissue, ulceration or necrosis of muscle or bone.

In another preferred embodiment, the radioactive soft tissue injury comprises chronic radiation subcutaneous tissue, muscle or bone damage.

In a further preferred embodiment, the radioactive soft tissue injury comprises chronic radiation subcutaneous tissue, muscle or bone ulceration, necrosis or fibrosis.

In a further preferred embodiment, the radioactive soft tissue injury is fibrosis of chronically radioactive subcutaneous tissue, muscle or bone.

In a further preferred embodiment, the radioactive soft tissue injury is post-radiation soft tissue inflammation and fibrosis. In a second aspect, the present invention provides a helper drug for improving the therapeutic effect of radiotherapy by using glycyrrhetinic acid or glycyrrhizic acid Applications in foods, health products, foods or food additives. In a third aspect, the present invention provides a method of treating radiation soft tissue damage, the method of treating the radioactive soft tissue injury with glycyrrhetinic acid or glycyrrhizic acid.

In a preferred embodiment, the glycyrrhetinic acid or glycyrrhizic acid is administered systemically or topically. Preferably, the glycyrrhetinic acid or glycyrrhizic acid is administered systemically. In a fourth aspect, the present invention provides a medicament for treating radiation soft tissue damage, comprising glycyrrhetinic acid or glycyrrhizic acid as an active ingredient.

In a preferred embodiment, the drug is a systemically administered drug or a locally administered drug, and preferably, the drug is a systemically administered drug.

In a specific embodiment, the drug is a systemically administered drug known to those skilled in the art such as tablets, capsules, solutions, suspensions, granules, granules, injections, and the like. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. DRAWINGS

Figure 1 shows that glycyrrhetinic acid reduces the skin score of mice 24 hours after 30Gy irradiation in the right hind limb, which proves that glycyrrhetinic acid can reduce the acute skin reaction after irradiation in mice;

Figure 2 shows the measurement of the degree of hindlimb contracture caused by soft tissue fibrosis after irradiation in mice. Figure 3 shows that glycyrrhetinic acid reduces the degree of contracture in mice 3 weeks after irradiation to 30Gy in the right hind limb, thus demonstrating that glycyrrhetinic acid can alleviate mice. Degree of soft tissue fibrosis 3 months after irradiation;

Figure 4 shows that glycyrrhetinic acid reduces the degree of contracture in mice 7 months after irradiation to 30 Gy in the right hind limb, which proves that glycyrrhetinic acid can reduce the degree of soft tissue fibrosis in mice 7 months after irradiation. detailed description

After extensive and in-depth research, the inventors found that glycyrrhizic acid and glycyrrhetinic acid have preventive and therapeutic radioactivity. The role of soft tissue damage, and low toxicity and safe use of glycyrrhizic acid and glycyrrhetinic acid, it may become a good drug for preventing and treating radioactive soft tissue damage, health care products, food or food additives. The present invention has been completed on this basis. Glycyrrhizic acid and glycyrrhetinic acid

Glycyrrhetinic acid and glycyrrhizic acid are the most important active ingredients in licorice, and glycyrrhizic acid can be metabolized to glycyrrhetinic acid in the body. Glycyrrhetinic acid and glycyrrhizic acid have anti-inflammatory, anti-viral and liver-protecting functions as well as enhancing immune function. Because glycyrrhetinic acid has steroid-like anti-inflammatory effects and adrenocortical-like pharmacological effects without serious adverse reactions, it is widely used in the treatment of various chronic hepatitis, improving liver function abnormalities, urticaria, etc. Cancer, interferon inducer, cellular immunomodulator and other functions. It has been reported in the literature that glycyrrhetinic acid has the effect of preventing and treating liver fibrosis (Deng Xiulan et al., Mechanism of action of glycyrrhetinic acid combined with tanshinone in preventing and treating liver fibrosis in rats, Chinese pharmacist, 2007, No. 8; Zhang Qisheng et al., Glycyrrhetinic acid In vivo study of targeting hepatic stellate cells for the treatment of hepatic fibrosis, Chinese Journal of Hepatology, No. 9 (2005), but the role of glycyrrhizic acid and glycyrrhetinic acid in the prevention and treatment of radioactive soft tissue injury has not been reported.

In addition, glycyrrhizic acid is gradually metabolized to glycyrrhetinic acid (which is its main functional group) due to hydrolysis of strongly acidic gastric juice in the body and degradation by intestinal flora, in other words, glycyrrhetinic acid is an active metabolite of glycyrrhizic acid. Therefore, glycyrrhizic acid can be reasonably regarded as a "prodrug" of glycyrrhetinic acid, and it is reasonably expected that the prodrug and the active drug will produce the same activity as those of ordinary skill in the art. Radioactive soft tissue injury

As used herein, "radioactive soft tissue injury" refers to damage to the skin, subcutaneous tissue, muscles, and even bone caused by a large dose or multiple doses of small doses (χ, α, β, γ rays, etc.). Among them, acute radioactive soft tissue injury refers to acute radioactive soft tissue inflammatory reaction and ulceration caused by a large dose or multiple small doses (χ, γ and β rays, etc.) externally applied to the body. Chronic radioactive soft tissue injury refers to chronic radioactive soft tissue ulcers, inflammatory reactions and fibrosis and necrosis caused by acute radioactive soft tissue injury or long-term exposure to low-dose radiation (occupational or iatrogenic). Fibrosis is different from ordinary inflammation or ulcer. The main pathological change is the increase of fibrous connective tissue in organ tissues, the decrease of parenchymal cells, and the continuous progression may cause organ structure damage and dysfunction, and even failure. Therefore, the treatment of fibrosis is often different from the treatment of inflammation or ulceration. Radioactive soft tissue damage as described above Released by radioactive materials (radioisotopes) such as uranium, plutonium and thorium; also by artificial radiation sources such as X-ray machines and radiotherapy instruments.

One of the mechanisms of radioactive soft tissue injury is capillary occlusion, extensive tissue fibrosis and direct cell injury. Among them, endocarditis occurs in small blood vessels and even larger endothelium. Vascular occlusion necrosis is an important factor affecting the pathological process in the late stage of tissue. Causes ulceration and poor wound healing. The second mechanism is that radiation causes DNA damage in the cells, causing duplication and error in the replication of the double helix, which results in poor proliferation of the irradiated cells, and a continuous error in immune damage induced by the "wrong protein" produced by DNA misconnection. Thus, the long-term injury reaction of radiation soft tissue injury and transient dermatitis for several months and years, resulting in structural damage and dysfunction of tissues and organs.

It will be apparent to those skilled in the art in view of the teachings of the present invention that the glycyrrhizic acid and glycyrrhetinic acid of the present invention can be applied to various radioactive soft tissue damage caused by various radioactive sources.

In a specific embodiment, the radioactive soft tissue injury described herein can be a radiation soft tissue injury at various parts of the body including, but not limited to, the head and neck, chest, abdomen, torso, limbs, hands and feet, and the like.

In a specific embodiment, the radioactive source of the radioactive soft tissue damage described herein may be a radioactive substance (radioisotope), such as uranium, plutonium or thorium, or may be produced by an artificial radiation source, such as an X-ray machine and a radiotherapy apparatus.

In a specific embodiment, the radioactive soft tissue damages described herein include, but are not limited to, electrons, neutrons, protons that directly form or indirectly release X, alpha, beta, and xenon rays. The pathophysiological mechanisms of soft tissue damage caused by various radiations are similar, due to radiation-induced nuclear double-strand breaks and/or blockade of mitosis, leading to the death of parenchymal or vascular cells or the induction of sustained immune killing.

In a specific embodiment, the radiation dose of the radioactive soft tissue injury described herein can be a single large dose or a divided small dose illumination, which can range from a few Gy to tens of Gy.

In a specific embodiment, the soft tissue injury includes, but is not limited to, an early inflammatory reaction, a medium fibrotic tissue replaces a functional substantial cell, and a late scar contracture, a tissue deformity, a dysfunction, etc., and the damage occurs. Various organizational levels, including but not limited to epithelial germinal layers, dermis and subcutaneous tissue and vascular bundles, and even bone damage. Application of glycyrrhizic acid and glycyrrhetinic acid

The present inventors have found that glycyrrhetinic acid or glycyrrhizic acid can inhibit post-radiation soft tissue fibrosis caused by radiation and The resulting dysfunction.

Glycyrrhizic acid and glycyrrhetinic acid have the effect of preventing or treating radioactive soft tissue damage. Therefore, glycyrrhizic acid and glycyrrhetinic acid can be used for the preparation of a medicament for preventing or treating radiation soft tissue damage.

It will also be understood by those skilled in the art that glycyrrhizic acid and glycyrrhetinic acid can also be used in the preparation of health supplements, food or food additives so that one can supplement it in the daily diet to protect against radiation soft tissue damage.

In a specific embodiment, glycyrrhizic acid and glycyrrhetinic acid are used to prevent or treat radiation soft tissue damage including, but not limited to, damage to subcutaneous tissue or bone caused by radiation.

The pathophysiological processes of the damage of subcutaneous tissue, muscle and even bone caused by ionizing radiation such as χ, α, β, γ ray are similar, so the glycyrrhizic acid and glycyrrhetinic acid of the present invention can prevent various radioactive soft tissue damage.

In a preferred embodiment, the radioactive soft tissue injury comprises acute radiation subcutaneous tissue, muscle or bone damage and chronic subcutaneous tissue, muscle or bone damage.

In a preferred embodiment, the radioactive soft tissue injury comprises radiation skin ulcers, chronic radiation skin ulcers or chronic soft tissue radiation fibrosis, more preferably chronic soft tissue radiofibrosis.

In a preferred embodiment, glycyrrhetinic acid or glycyrrhizic acid can be prepared as a radiotherapy auxiliary drug, considering that glycyrrhetinic acid or glycyrrhizic acid can reduce the side effects caused by radiotherapy and improve the quality of life of the patient. Patients who were administered glycyrrhetinic acid or glycyrrhizic acid were more tolerant to radiation than patients who did not receive glycyrrhetinic acid or glycyrrhizic acid, thereby increasing the dose of radiation while applying glycyrrhetinic acid or glycyrrhizic acid. Improve the efficacy of radiotherapy.

Moreover, in view of the teachings herein and the prior art, it will be readily apparent to those skilled in the art that glycyrrhetinic acid or glycyrrhizic acid can be prepared in a conventional manner, but not limited to, tablets, capsules, solutions, transdermal patches, A pharmaceutical dosage form such as a granule or an injection; or a dosage form prepared by, but not limited to, a beverage, a granule, or the like.

One skilled in the art will also appreciate that one or more pharmaceutically or food or nutritionally acceptable carriers may be selected depending on the particular need, including but not limited to diluents, excipients, fillers, sticks. A wetting agent, a disintegrant, an absorption enhancer, a surfactant, an adsorption carrier, a lubricant, and the like. Advantages of the invention:

1. The glycyrrhetinic acid and glycyrrhizic acid used in the present invention have anti-soft tissue damage (e.g., chronic fibrosis), particularly anti-radiation soft tissue damage;

2. The glycyrrhetinic acid and glycyrrhizic acid used in the invention have low cost, exact curative effect and low toxicity for long-term application; 3. The glycyrrhetinic acid or glycyrrhizic acid used in the present invention can be prepared as a health care product, food or food additive for preventing or treating radioactive soft tissue damage, and is easy to take. Example 1 Experimental animals: 8 week old C57BL/6 male mice (purchased from the Experimental Animal Center of Shanghai Institute of Biological Sciences). The animals were randomly divided into groups in the observation observation room for 3 days before administration. The average number of cages per cage was 25 degrees at room temperature, the relative humidity was 50-70%, and the light-dark cycle was 12 hours.

Irradiation instrument: Electron linear accelerator (SIMENS, PRIMUS 600, Germany), produced X-ray dose rate of 2 Gy / min.

Animal modeling and drug intervention: Experimental animals were randomly divided into 4 groups: normal control group, model solvent group, glycyrrhetinic acid treatment group and positive drug Celebrex treatment group. The model solvent group, the glycyrrhetinic acid treatment group and the Celebrex treatment group received a single irradiation of 30 Gy in the right hind limb. The rats were fixed in a specially designed fixture during the irradiation. After the irradiation, the glycyrrhetinic acid treatment group was orally administered with glycyrrhetinic acid 30 mg on the same day. /kg (PBS buffer solution), Celebrex 30 mg/kg was given orally on the day of the Celebrex treatment group, and the same 0.2 ml PBS buffer was given to the normal control group and the model solvent group three times a week for 24 days.

Four days after the irradiation, four researchers observed the skin reaction of the right hind limb, and the inflammation score was taken as the average value. The grading standards for radiation dermatitis were as follows:

The observation of radiation dermatitis in the right hind limb of mice showed that the skin score of the glycyrrhetinic acid group was lower than that of the solvent control group and the Celebrex group, and the P value was less than 0.05, indicating that the acute skin inflammation of the glycyrrhetinic acid group was lighter than the model solvent group and the positive drug. The Xilezhen group, the results are shown in Figure 1.

Example 2

Experimental animals: Same as Example 1. Irradiation instrument: Same as in Example 1.

Animal Modeling and Drug Intervention: Experimental animals were randomly divided into 4 groups: normal control group, model solvent group, glycyrrhetinic acid treatment group and positive drug Celebrex treatment group. The model solvent group, the glycyrrhetinic acid treatment group and the positive drug Celebrex treatment group received a single irradiation of 30 Gy in the right hind limb. The rats were fixed in a specially designed fixture during the irradiation, and the glycyrrhetinic acid treatment group was orally administered with glycyrrhetinic acid on the day after irradiation. 25 mg/kg (PBS buffer solution), Celebrex 30 mg/kg was given orally on the day of the Celebrex treatment group, and the same volume of PBS buffer was given to the normal control group and the model solvent group three times a week for a total of 28 times. day.

After 3 months of irradiation, the right hind limb fibrosis (degree of right hind limb contracture) was observed. The observed index was: the difference between the length of the right hind limb and the normal left hind limb. The mouse was fixed to a specially designed quantitative standard ruler and kept parallel to the ruler. The position of the mouse ankle joint was used as the center of positioning, and the legs and ankles were gently pulled down at the same time, until the corresponding resistance was greatly increased. Stop pulling, measure the distance between the right leg ankle joint extension point and the left leg ankle joint positioning point and define it as the difference between the length of the right right hind limb and the normal left hind limb, as shown in Figure 2.

The observation of radiofibrosis in the right hind limb of mice showed that the difference in length of hind limbs of the glycyrrhetinic acid group was smaller than that of the solvent control group and the Celebrex group (P value was less than 0.05), while the glycyrrhetinic acid group was larger than the blank control group (P> 0.05). The results showed that the degree of chronic soft tissue radiofibrosis in the glycyrrhetinic acid group was lighter than that in the model solvent group and the positive drug Celebrex group. The results are shown in Fig. 3.

Example 3

Experimental animals: Same as Example 1.

Irradiation instrument: Same as Example 1.

Animal modeling and drug intervention: Experimental animals were randomly divided into 4 groups: normal control group, model solvent group, glycyrrhetinic acid treatment group and positive drug Celebrex treatment group. The model solvent group, the glycyrrhetinic acid treatment group and the positive drug Celebrex treatment group received a single irradiation of 50 Gy in the right hind limb. The rats were fixed in a specially designed fixture during the irradiation, and the glycyrrhetinic acid treatment group was orally administered with glycyrrhetinic acid on the day after irradiation. 40 mg/kg (PBS buffer-assisted solution), Celebrex 50 mg/kg was given orally on the day of the Celebrex treatment group, and the same volume of PBS buffer was given to the normal control group and the model solvent group three times a week for a total of 28 times. day.

After 7 months of irradiation, the right hind limb fibrosis (degree of right hind limb contracture) was observed, and the observation index and measurement method were the same as in Example 2.

Long-term radioactive fibrosis in the right hind limb of mice showed that the difference in length of the hind limbs of the glycyrrhetinic acid group was small. In the solvent control group (P<0.05), the glycyrrhetinic acid group was larger than the Celebrex group (P>0.05). The results showed that the degree of chronic soft tissue radiofibrosis in the glycyrrhetinic acid group was lighter than that in the model solvent group, and the results are shown in Fig. 4.

In summary, the glycyrrhetinic acid and glycyrrhizic acid of the present invention have anti-soft tissue damage (for example, long-term fibrosis), especially radioactive soft tissue damage, and the curative effect is exact, and the long-term application toxicity is small, so glycyrrhetinic acid or glycyrrhizic acid The use of a medicament for preventing or treating radiation soft tissue damage can also be used for the preparation of health care products, foods or food additives for treating radiation soft tissue damage. Comparative example

The present inventors also treated glycyrrhetinic acid (topical and oral) with conventional radiation dermatitis therapeutic drugs such as glucocorticoids (topical) for the treatment of chronic soft tissue radiofibrosis.

The results showed that the therapeutic effect of conventional radioactive dermatitis drugs on chronic soft tissue radiofibrosis was not as good as that of glycyrrhetinic acid, and the systemic administration of glycyrrhetinic acid was superior to topical treatment for chronic soft tissue radiofibrosis. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the present invention.

Claims

Rights request

I. Application of glycyrrhetinic acid or glycyrrhizic acid in the preparation of drugs, health products, food or food additives for preventing or treating radiation-induced soft tissue damage.

2. The application according to claim 1, characterized in that the medicine, health product, food or food additive is used for auxiliary treatment of radiotherapy.

3. The application according to claim 1 or 2, characterized in that the radioactive soft tissue damage includes damage to subcutaneous tissue, muscles or bones caused by radiation.

4. The application according to claim 3, wherein the radioactive soft tissue damage includes acute radioactive subcutaneous tissue, muscle or bone damage.

5. The application according to claim 4, wherein the radiation soft tissue damage includes acute radiation ulceration or necrosis of subcutaneous tissue, muscle or bone.

6. The application according to claim 3, wherein the radioactive soft tissue damage includes chronic radioactive subcutaneous tissue, muscle or bone damage.

7. The application according to claim 6, characterized in that the radiation soft tissue damage includes chronic radiation ulcers, necrosis or fibrosis of subcutaneous tissue, muscles or bones.

8. The application according to claim 7, characterized in that the radiation soft tissue damage is chronic radiation fibrosis of subcutaneous tissue, muscle or bone.

9. The application according to claim 8, characterized in that the radiation soft tissue damage is post-radiation soft tissue fibrosis.

10. Application of glycyrrhetinic acid or glycyrrhizic acid in the preparation of auxiliary drugs, health products, food or food additives to improve the efficacy of radiotherapy.

II. A method for treating radioactive soft tissue damage, characterized by using glycyrrhetinic acid or glycyrrhizic acid to treat the radioactive soft tissue damage.

12. The treatment method according to claim 11, wherein the glycyrrhetinic acid or glycyrrhizic acid is administered systemically or locally; preferably, the glycyrrhetinic acid or glycyrrhizic acid is administered systemically.

13. A drug for treating radiation-induced soft tissue damage, characterized in that the drug contains glycyrrhetinic acid or glycyrrhizic acid as an active ingredient.

14. The drug according to claim 13, characterized in that the drug is a drug administered systemically or a drug administered locally; preferably, the drug is a drug administered systemically.