KR20050062256A - Hematosis composition comprising dang­gui for treating anemia caused by administrating anticancer - Google Patents

Abstract

The present invention relates to a hematopoietic agent for the treatment of anemia by administration of anticancer agent containing Angelica extract.

Angelica extract of the present invention has a significant effect on the recovery of leukocyte count, erythrocyte volume, hemoglobin, etc. against anemia induced by cyclophosphamide, and also as a natural herbal substance extracted from Angelica known as a herbal medicine, and has no side effects. It can be usefully used as a hematopoietic composition for the treatment of anemia by administration.

Description

Hematopoietic agent for the treatment of anemia by the administration of anticancer agent containing Angelica gigas {HEMATOSIS COMPOSITION COMPRISING DANG D GUI FOR TREATING ANEMIA CAUSED BY ADMINISTRATING ANTICANCER}

The present invention relates to a hematopoietic agent, and more particularly to a hematopoietic agent for the treatment of anemia by administration of an anticancer agent.

Cancer is a generic group of diseases that can begin by uncontrolled cell proliferation, invade and destroy new surroundings, or create new growth sites.

The development of cancer has developed over the last decade, despite significant advances in the regulation of cell cycles and apoptosis and the search for new targets, including oncogenic and cancer suppressor genes, to conquer cancer. It is increasing as it becomes.

Currently, the treatment of cancer patients is dependent on chemotherapy by surgical surgery, radiation therapy and the administration of about 40 types of cytotoxic drugs. Among them, chemotherapy for administering anticancer drugs is most often used as a treatment for cancer, and anticancer drugs exhibit cytotoxicity not only to cancer cells but also to normal cells, causing various side effects. It is reported to be accompanied by a disorder.

Cyclophosphamide, an anticancer drug, is an alkylated drug, and its side effects include nausea and vomiting due to acute toxicity, delayed toxicity suppresses the increase of peripheral blood count, leukopenia due to severe myelosuppression upon overdose. Causes thrombocytopenia and bleeding, leading to hemorrhagic cystitis. These side effects cause cancer patients to experience nausea and vomiting, especially anemia, after taking anticancer drugs.

In particular, anemia caused by cyclophosphamide administration is characterized by a decrease in platelets due to bone marrow failure caused by anticancer agents, unlike general anemia caused by lack of blood (iron). Specifically, such bone marrow failures cause an increase in blood count, leukopenia, thrombocytopenia and bleeding, and hemorrhagic cystitis. Specifically, a gradual decrease in hemoglobin concentration was reported in rats treated with cyclophosphamide [Latha PG, Panikkar KR., Phytother Res. , 1999, 13 (6), 517-520].

As described above, anemia caused by the administration of anticancer drugs has a problem that affects the energy level, activity and quality of life of cancer patients as well as pain caused by other side effects in cancer patients.

An object of the present invention is to solve the above problems, to provide a hematopoietic composition that can be used for the prevention and treatment of anemia caused by the administration of an anticancer agent.

In order to achieve the above object, the present invention provides a hematopoietic composition containing Angelica extract.

Hereinafter, the present invention will be described in detail by way of examples.

The Angelica extract of the present invention uses the dried Angelica extract obtained by hot water extraction using distilled water and then concentrated under reduced pressure. In this case, the donkey may use all the donkeys used in oriental medicine or other fields, preferably Angelica gigas N _AKAI , Angelica sinensis D _IELS and Angelica acutiloba K _ITAGAWA alone Or it can mix and use.

Such Angelica extract is effective in preventing and treating anemia caused by administration of anticancer drugs.

Specifically, the donkey extract administration group for the anemia caused by the administration of anticancer agents has a significant recovery effect on the items such as red blood cell volume change, red blood cell number change, hemoglobin concentration change, white blood cell count reduction (see Fig. 1).

In addition, hemoglobin extract administration group showed significant recovery effect on blood AST (GOT), iron, Trasferrin saturation, ALT (GPT), vitamin B-12, etc.

Vitamin B-12 is an essential nutrient for normal blood production and nerve function. Most deficiencies cause pernicious anemia. Insufficient vitamin B-12 causes DNA subsynthesis to occur, resulting in massive subblast anaemia, and hematologic symptoms are restored to normal even when vitamin B-12 is administered to patients who lack vitamin B-12. If you are not fully recovered from neurological disorders is known as an important nutrient. The Angelica extract of the present invention significantly increases the vitamin B-12 concentration after administration of anticancer drugs, and thus may have an effect on blood production.

In addition, the Angelica extract of the present invention can alleviate the side effects caused by administration of anticancer drugs. Specifically, the Angelica extract can alleviate the weight loss caused by the administration of an anticancer agent, and also shows a visually favorable difference in the dropout of hair and the moisture of the hair. In particular, in the case of dietary intake, when the Angelica extract was administered after the administration of the anticancer agent, the dietary efficiency for body weight was high even though there was no difference in dietary intake compared to the control group. This is not because the weight was increased due to dietary intake, it can be seen that the administration of the Angelica extract induced weight gain by inhibiting the weight loss side effects by anticancer drugs.

The compound of Formula 1 may be administered in various oral and parenteral formulations during clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used, may be used. It is manufactured by. Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and when the weight is 70 kg based on an adult patient Generally, it is 0.01-1000 mg / day, Preferably it is 0.1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

However, the following examples are merely to illustrate the present invention is not limited to the contents of the present invention.

Example 1 Preparation of Angelica Extract

Each of the Chinese Angelica Angelica, Chinese Angelica Angelica, and Chinese Angelica Angelica was cut into 100 g of a round-bottomed flask, 2 liters of distilled water was added, and a cooler was attached and heated for 2 hours. After heating, the filtrate was filtered under reduced pressure with a filter paper and concentrated under reduced pressure using a rotary vaccum evaporator (Eyela, Japan), and the concentrate was freeze-dried. At this time, the yield was 22.5%, Angelica extract, 26.6% and Angelica extract 27.5%.

Preparation Example 1 Manufacturing Method of Capsule

10 mg of Angelica extract of Example 1 was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

The components of the powder and capsules are as follows.

Angelica extract of Example 1 10 mg ··············

Lactose ························ 14.8 mg

10.0 mg of polyvinylpyrrolidone

Magnesium Stearate 0.2 mg

Preparation Example 2 Manufacturing Method of Injection Solution

An injection was prepared by containing 50 mg of the compound of Example 1, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O, and 2974 mg of distilled water. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

Angelica extract of Example 1 50 mg

Mannitol 180 mg

Na ₂ HPO ₄ · 12H ₂ O ·············· 26

Distilled water 0.2 mg

Experimental Example 1 Measurement of Weight and Dietary Intake

The experimental animals were supplied with 4 week-old Sprague-Dawley male rats (Samtako, Korea) and a solid feed (Samyang Combined Animals, Samyang Oil & Fat Feed, Korea) and water for at least 1 week in the laboratory environment (temperature 22 ± 2 ° C., humidity 55 ± 5%, day / night 12 hours) before use.

Normal group (8), anemia-induced-normal diet-saline (control, 8 animals), anemia-induced-normal diet-canine ear extract administration group (AG, 8), anemia-induced-normal diet-Chinese Angelica extract administration group ( AS, 8), and anemia-induced-normal diet-per-ear extract administration group (AA, 8).

In the experimental group, anemia was induced intraperitoneally with 30 mg / kg B.W./day of cyclophosphamide (Allaloxan 500 mg FTC). Chinese Angelica, Chinese Angelica, and Korean Angelica extract were orally administered at 1 g / kg B.W./day for 14 days.

All animal diets were fed by free intake. During the experiment, the intake was measured daily, and the body weight was measured every two days. The food efficiency ratio (FER) was calculated by dividing the weight gain during the experiment period by the dietary intake during the experiment period from the start of the experiment to the sacrifice day as a total experiment period (see Equation 1 below).

FER = weight gain (g / day) / dietary intake (g / day)

The experimental results were expressed as mean ± standard error (Mean ± SD). When testing the difference between the control group and the experimental group, the student's t-test was used to determine statistically significant difference when the P value was less than 0.05. It was.

The results are shown in Table 1 below.

Experimental group Initial weight (g) Final weight (g) Weight gain (g / day) Dietary Intake (g / day) Normal 126.80 ± 5.40 206.80 ± 20.47 6.10 ± 0.85 21.22 ± 0.49 Control 134.50 ± 3.67 ^# 170.00 ± 12.20 ^### 2.77 ± 0.55 ^### 9.25 ± 0.07 ^### AG 134.25 ± 7.74 188.00 ± 10.81 ^** 4.05 ± 0.50 ^** 9.17 ± 0.75 ^** AS 135.04 ± 5.58 185.51 ± 11.35 ^* 3.92 ± 0.73 ^* 10.01 ± 0.35 ^* AA 132.53 ± 4.62 179.53 ± 9.47 3.46 ± 0.54 10.24 ± 0.61  The value is mean ± standard deviation. # Indicates a significant difference to the normal group values. (#: p <0.05; ###: p <0.001) * indicates that there is a significant difference to the control value. (*: p <0.05; **: p <0.01; ***: p <0.001)

As shown in Table 1, the weight of the beginning of the experiment was significantly lower in the normal group, but the final body weight of the experiment was significantly lower in the control group administered cyclophosphamide in the normal diet group than the normal group. In the normal diet group, after the cyclophosphamide administration, the Angelica gigas group (AG) had a significantly higher body weight than the control group.

It was observed that the weight gain was significantly decreased in the cyclophosphamide-administered group compared to the normal group, and the weight gain was significantly higher in the Angelica gigas group (AG) compared to the control group in which the cyclophosphamide was administered. There was also significant weight gain in the group receiving AS) and AA. Most preferably, the Angelica gigas group had the highest significance.

Dietary intake was significantly lower in the control group treated with cyclophosphamide compared to the normal group. There was no difference in dietary intake between the control group and the control group after the administration of cyclophosphamide (AG) in the normal group, but there was a significant increase in the group receiving the Chinese donkey (AS) and the daily donkey (AA).

Experimental Example 2 Blood Analysis

The experimental group used the same thing as used in Experimental Example 1 above. After 14 days of the experiment, blood was collected at the expense of the experimental group.

(1) blood collection

5 mL of blood was collected by the heart puncture method at the time of sacrifice, and 1 mL of the sample was shaken to be homogeneous in an EDTA-treated tube and stored at 4 ° C. to measure CBC (complete blood count) within 48 hours. The remaining blood was collected in EDTA free tubes for biochemical measurement and centrifuged at 3,000 rpm for 15 minutes to obtain serum. The feed was stored at -70 ° C until analysis.

(2) blood analysis

Whole blood in the EDTA tube contains: red blood cells (RBC), hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume (MCV), and mean hemoglobin concentration Mean corpuscular hemoglobin concentration (MCHC) was examined and measured using an automatic blood cell counter (Sysmex NE 8000, Toa Medical Electronics Co., Japan).

Serum iron concentration was measured using SCIDIA Fe-760 reagent (Youngyeon Chemical, Korea), and total iron binding capacity (TIBC) was measured by an automatic biochemical analyzer (Hitachi 747, Hitachi Co., Japan). Transferrin saturation (TS) was measured by Nephelometer (Behring Nephelometer, Behring, West Germany). Vitamin B ₁₂ was measured with an ADVIA centaur (Bayer Corporation Tarrytown NY 10591-5097, USA) using a VB12 reagent (Bayer Corporation 333 Coney Street E Walpole MA 02032, ADVIA centaur, USA).

Statistical treatment was performed in the same manner as in Experiment 1.

The results are shown in FIGS. 1A-1F. Specifically, FIG. 1A is a graph showing changes in red blood cells (RBC) for each experimental group, FIG. 1B is a change in white blood cell count, FIG. 1C is a change in red blood cell volume (Hct), and FIG. 1D is a change in hemoglobin (Hgb) concentration. FIG. 1E is a graph showing changes in mean red blood cell volume (MCV) and FIG. 1F is a change in mean red blood cell hemoglobin concentration (MCHC).

The results obtained from the results in FIGS. 1A to 1F are as follows.

Red blood cell (RBC) changes

As shown in FIG. 1A, the control group showed a significant decrease of 5.74 ± 0.43 (× 10 ⁶ ) compared to 6.72 ± 0.27 (× 10 ⁶ ) in the normal group (p = 0.004), and the Angelica gigas group (AG) Significant recovery effect was observed at 6.91 ± 0.97 (× 10 ⁶ ) (p = 0.05), and 6.15 ± 0.33 (× 10 ⁶ ) in Chinese donkey group (AS) and 6.28 ± 0.64 in daily donkey group (AA) The recovery effect was observed at (× 10 ⁶ ).

Leukocyte count change

As shown in FIG. 1B, the control group showed a significant decrease of 2.14 ± 0.38 (× 10 ³ ) compared to the normal leukocyte count of 5.96 ± 0.90 (× 10 ³ ) (p = 0.002). 4.00 ± 0.62 (× 10 ³ ) (p = 0.0001) in, 5.25 ± 1.29 (× 10 ³ ) (p = 0.0005) in Chinese donkey group (AS) and 3.51 ± 1.14 (× 10 ³ ) in single donor group (AA) (p = 0.01), significant recovery effect was observed.

Hematocrit (Hct) change

As shown in FIG. 1C, the control group showed a significant decrease of 40.80 ± 1.92% compared to 45.80 ± 2.49% of erythrocyte volume in the normal group (p = 0.01), and 48.17 ± 6.97% (p) in the Angelica gigas group (AG). = 0.05), 43.50 ± 2.51% (p = 0.05) in the Chinese Angelicai group (AS) and 43.86 ± 1.77% (p = 0.02) in the Chinese Angelicai group (AA) were observed.

Hemoglobin (Hgb) Concentration Changes

As shown in FIG. 1D, the control group showed a significant decrease of 11.83 ± 0.87 g / dL compared to 14.10 ± 0.52 g / dL in normal group (p = 0.0002), and 13.55 ± 1.69 in AG group g / ㎗, 12.98 ± 0.78 g / ㎗ (p = 0.02) in Chinese donkey group (AS) and 12.90 ± 0.69 g / ㎗ (p = 0.03) in daily donkey group (AA) were observed. .

Mean corpscular volume (MCV) change

As shown in FIG. 1E, the control group showed an increase of 70.38 ± 3.74 compared to the average erythrocyte volume of 68.20 ± 2.17 in the normal group, 71.00 ± 2.67 in the Angelica gigas group (AG), 70.88 ± 3.23 in the Chinese camouflage group (AS) and In the AA group, significant recovery effect was observed at 72.63 ± 1.51.

Changes in mean corpuscular hemoglobin concentration (MCHC)

As shown in FIG. 1F, the control group showed a significant decrease of 30.13 ± 0.35 compared to the mean erythrocyte hemoglobin concentration of 31.00 ± 0.71 in the normal group (p = 0.047). In AS, 29.75 ± 0.46 and in the AA group, 29.25 ± 0.71, no recovery effect was observed.

Experimental Example 5 Oral Acute Toxicity in Rats

Acute toxicity test was performed using 6-week-old specific pathogen-free (SPF) SD rats. Two animals per group were suspended orally once with Compound 1 of the present invention in 0.5% methylcellulose solution. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed, and hematological and hematological examinations were performed.

As a result, no clinical symptoms or dead animals were found in all animals treated with the test substance, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. As a result, all of Example 1 of the present invention showed no change in toxicity up to 1000 mg / kg in the let, and the minimum lethal dose (LD ₅₀ ) of oral administration was found to be a safe substance of 1000 mg / kg or more in the let.

As described above, the Angelica extract of the present invention has a significant effect on the recovery of leukocyte count, erythrocyte volume, hemoglobin, etc. for anemia induced by cyclophosphamide, and as a hematopoietic composition for treating anemia by administration of anticancer drugs. It can be useful and can also solve the problem of anorexia, a side effect of chemotherapy.

In particular, the Angelica extract is a natural herbal substance extracted from Angelica known as a herbal medicine has no side effects there is an advantage that patients receiving chemotherapy can be administered with confidence.

Figure 1a is a graph showing the red blood cells (RBC) change for each experimental group of the present invention,

Figure 1b is a graph showing the change in the white blood cell count for each experimental group of the present invention,

Figure 1c is a graph showing the change in red blood cell volume (Hct) for each experimental group of the present invention,

Figure 1d is a graph showing the change in hemoglobin (Hgb) concentration for each experimental group of the present invention,

Figure 1e is a graph showing the average red blood cell volume (MCV) change for each experimental group of the present invention,

Figure 1f is a graph showing the average hematopoietic hemoglobin concentration (MCHC) change for each experimental group of the present invention.

At this time, the numerical values in the figures are mean ± standard deviation.

# Indicates a significant difference to the normal group values,

(#: p <0.05; ###: p <0.001)

* Indicates significant difference to the control values.

(*: p <0.05; **: p <0.01; ***: p <0.001)

Claims (5)

Hematopoietic composition comprising Angelica extract as an active ingredient. The hematopoietic composition according to claim 1, wherein the donkey extract is dried by hot water extraction using distilled water and then concentrated under reduced pressure. The hematopoietic composition according to claim 2, wherein the donkey is selected from the group consisting of true donkey, Chinese donkey and monodon. The hematopoietic composition according to claim 1, wherein the hematopoietic composition is used for preventing and treating anemia caused by administration of an anticancer agent. The hematopoietic composition according to claim 4, wherein the anticancer agent is cyclophosphamide.