Multi-dimensional traditional Chinese medicine composition for preventing and treating myelosuppression, herbal preparation and application

Abstract

The invention provides a multi-vitamin traditional Chinese medicine composition for preventing and treating myelosuppression. The multi-vitamin traditional Chinese medicine composition comprises the following components in parts by weight: 25-35 parts of Chinese dates, 18-25 parts of suberect spatholobus stems, 6-15 parts of fructus psoraleae, 6-15 parts of glossy privet fruits and 10-20 parts of acanthopanax roots. According to the multi-dimensional traditional Chinese medicine composition for preventing and treating myelosuppression, the goals of bone marrow protection and multi-line blood cell rising can be planned as a whole, and the myelosuppression can be prevented and treated in a multi-dimensional manner. The invention further provides a multi-dimensional herbal preparation for preventing and treating myelosuppression and application of the multi-dimensional traditional Chinese medicine composition for preventing and treating myelosuppression in preparation of myelosuppression drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicines, and in particular to a multi-dimensional traditional Chinese medicine composition for preventing and treating bone marrow suppression, a herbal preparation and an application thereof. Background Art

[0002] Bone marrow suppression is the most common and important complication of tumor radiotherapy and chemotherapy. The significant decrease in peripheral blood leukocytes, hemoglobin, and platelets can cause fatal infections and bleeding. The occurrence of anemia affects the efficacy of radiotherapy and the implementation of subsequent chemotherapy, severely limiting the progress and prognosis of tumor treatment. The treatment-related mortality rate associated with severe bone marrow suppression is 4% to 12% worldwide, and most of the reasons are various difficult-to-control infections caused by severe bone marrow suppression and granulocytopenia. In addition, fever, bleeding, and anemia during the bone marrow suppression period require patients to be hospitalized for systemic anti-infection treatment. Hemostasis and blood transfusion during the period indirectly increase the treatment costs of tumor patients and worsen the quality of life of patients. Therefore, bone marrow suppression is a dangerous obstacle that interferes with clinical oncologists in implementing radiotherapy and chemotherapy treatment plans, and it is also a fatal threat to the recovery of tumor patients.

[0003] Studies have found that the main mechanisms of bone marrow suppression caused by radiotherapy and chemotherapy are as follows:

[0004] 1. Chemotherapy damages hematopoietic cells: damage to multipotent hematopoietic stem cells (HSC) and hematopoietic progenitor cells leads to bone marrow suppression (HPC);

[0005] 2. Chemotherapy destroys the hematopoietic microenvironment: apoptosis and aging of bone marrow stromal cells, reduced osteogenic differentiation and increased adipose differentiation, inhibiting bone marrow hematopoiesis; multiple cytokine disorders, thus affecting HSC / HPC differentiation, leading to bone marrow suppression; changes in signal pathways; destruction of sinusoidal blood vessels, consumption of stromal cells, leading to poor hematopoietic "soil", affecting hematopoiesis.

[0006] At present, both drug and non-drug treatments for myelosuppression in clinical practice cannot meet the medication needs of clinicians and the compliance requirements of patients. The main defects are mainly reflected in the following aspects:

[0007] 1. It cannot solve the problems of interruption, postponement, and reduction of radiotherapy and chemotherapy caused by bone marrow suppression;

[0008] 2. High prices. Whether it is blood component transfusion, hematopoietic factor or peripheral hematopoietic stem cell transplantation, although the efficacy is certain, it requires high costs. The existing bone marrow protective agents with definite efficacy cost tens of thousands of yuan per cycle.

[0009] 3. Single effect. Both biological agents and chemical drugs can only target a certain type of cytopenia. They have a single effect and cannot coordinate bone marrow protection and blood cell increase.

[0010] 4. The side effects are significant. Liver and kidney damage and musculoskeletal pain are common side effects of existing white blood cell-raising drugs, while drugs that increase platelets and promote red blood cell production are prone to cause thrombosis.

[0011] In view of this, it is urgent to research and develop natural medicines that are economical, effective, take into account multiple blood cells and have minimal adverse reactions to preserve the marrow and produce blood. Summary of the invention

[0012] The technical problem to be solved by the present invention is to provide a Chinese medicine composition and herbal preparation for multi-dimensional prevention and treatment of bone marrow suppression, which can coordinate the goals of bone marrow protection and multi-lineage blood cell increase, and prevent and treat bone marrow suppression in a multi-dimensional manner.

[0013] The first aspect of the present invention is to provide a multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression, comprising the following components by weight:

[0014] 25-35 parts of jujube, 18-25 parts of Millettia reticulata, 6-15 parts of Psoralea corylifolia, 6-15 parts of Ligustrum lucidum fruit, and 10-20 parts of Acanthopanax senticosus.

[0015] Preferably, a multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression comprises the following ingredients by weight:

[0016] 30 parts of jujube, 20 parts of Millettia reticulata, 10 parts of Psoralea corylifolia, 10 parts of Ligustrum lucidum, and 15 parts of Acanthopanax senticosus.

[0017] The second aspect of the present invention is to provide a multi-dimensional herbal preparation for preventing and treating bone marrow suppression, wherein the herbal preparation comprises active pharmaceutical ingredients, and the active pharmaceutical ingredients are prepared from the traditional Chinese medicine composition described in the first aspect.

[0018] Furthermore, the herbal preparation also includes pharmaceutically acceptable excipients.

[0019] Furthermore, the herbal preparation is a decoction, a syrup, a granule, a capsule, a tablet, a soup, a powder, a pill, an oral liquid, or a suspension.

[0020] Furthermore, the herbal preparation is added as an effective additive into food or health products, such as, but not limited to, protein supplements or enteral nutrition agents.

[0021] The third aspect of the present invention is to provide a multi-dimensional Chinese medicine composition for preventing and treating myelosuppression and its use in preparing myelosuppression drugs.

[0022] Compared with the prior art, the multi-dimensional Chinese medicine composition and herbal preparation and application for preventing and treating myelosuppression provided by the present invention have the following beneficial effects:

[0023] 1. The multi-dimensional Chinese medicine composition for preventing and treating myelosuppression provided by the present invention is based on the perspective of traditional Chinese medicine: the jujube in the prescription is sweet, flat in nature, enters the spleen and stomach meridians, has the effects of tonifying the middle qi, nourishing blood and calming the mind, can significantly improve nausea and vomiting and decreased appetite after radiotherapy and chemotherapy, and strengthens the function of the spleen and stomach to receive the essence of water and grain, which is the main medicine in the prescription. Acanthopanax invigorates qi and strengthens the spleen, helps jujube invigorates qi and nourishes blood, Millettia reticulata activates blood circulation and nourishes blood, and helps jujube nourish blood. The combination of the two can not only nourish qi and nourish blood, but also improve local blood circulation and maintain the balance of peripheral blood homeostasis, and are both ministerial medicines in the prescription. Psoralea corylifolia nourishes the kidney and warms the yang, enters the kidney meridian, and the kidney governs the bones. It can improve the bone marrow suppression after radiotherapy and chemotherapy. The kidney is the innate foundation. The abundance of kidney yang can promote the gasification of the heart and lungs, so that the water and grain essence received by the spleen and stomach are fully transformed into blood; Ligustrum lucidum is cool in nature, sweet and bitter in taste, and enters the liver and kidney meridians. It can nourish blood and soften the liver to prevent excessive liver qi from hurting the spleen, and it can nourish kidney water and replenish the original yin in the kidney. When used with Psoralea corylifolia, it can replenish the yin and yang in the kidney, so that the bone marrow suppression after radiotherapy and chemotherapy is significantly improved. The two are combined as adjuvant drugs. The combination of these drugs can strengthen the spleen and stomach, enhance the gasification of the heart and lungs, significantly improve blood cells and various components of blood cells, and restore anemia after radiotherapy and chemotherapy.

[0024] From the perspective of Western medicine: Millettia reticulata, Psoralea corylifolia, and Ligustrum lucidum in the prescription can promote the proliferation of hematopoietic stem cells and hematopoietic progenitor cells, serving as "seeds" to promote the proliferation of hematopoietic cells; Millettia reticulata can inhibit cell apoptosis and reduce the impact of apoptosis on bone marrow stromal cells; Millettia reticulata, jujube, and Ligustrum lucidum can promote the function of lymphocytes, promote the release of cytokines, and fight against multiple cytokine disorders, thereby ensuring the normal differentiation of hematopoietic stem cells and progenitor cells; Acanthopanax senticosus can normalize vascular function and ensure the health of the "soil" in the hematopoietic microenvironment. Therefore, this prescription takes into account both the "seeds" and "soil" in the hematopoietic system, which is beneficial for preventing and treating bone marrow suppression.

[0025] Second, the multi-dimensional Chinese medicine composition for preventing and treating myelosuppression of the present invention, Ligustrum lucidum and Psoralea corylifolia can promote leukocyte production; jujube can promote lymphocyte proliferation; Ligustrum lucidum can promote erythroid proliferation, and at the same time can increase the secretion of EPO analogs, further strengthening its function of promoting erythroid hematopoiesis; finally, Ligustrum lucidum can also promote platelet production, and with the regulation of Acanthopanax senticosus and Psoralea corylifolia on platelet function, platelet aggregation is inhibited, and platelet loss is reduced, thereby minimizing the decline in the number of platelets in the blood. Therefore, the Chinese medicine composition of the present invention can coordinate the goals of bone marrow protection and multi-lineage blood cell elevation, and prevent and treat myelosuppression in multiple dimensions.

[0026] 3. The multi-dimensional Chinese medicine composition for preventing and treating myelosuppression provided by the present invention focuses on the prevention of myelosuppression, preventing the occurrence of myelosuppression, and reducing the severity of myelosuppression, so as to fundamentally solve the problems of interruption, postponement, and reduction of radiotherapy and chemotherapy caused by myelosuppression.

[0027] 4. The multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression provided by the present invention is composed of five Chinese herbal medicines and has a lower cost than existing bone marrow protection treatments.

[0028] Fifth, the multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression provided by the present invention has the effect of protecting liver and reducing the survival and death of liver cells; Acanthopanax senticosus combined with Millettia reticulata can well prevent musculoskeletal pain during the process of increasing white blood cells by promoting blood circulation and unblocking collaterals; the problem of thrombosis that is prone to occur during the process of increasing platelets and promoting erythropoiesis can be prevented and treated by inhibiting platelet aggregation by Psoralea corylifolia; and jujube is a medicinal and edible ingredient. Therefore, the Chinese medicine composition of the present invention has few side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0030] Figure 1 It is a diagram showing the effects of the Chinese medicine composition of the present invention on five types of blood cells when used to prevent bone marrow suppression caused by 5-fluorouracil (5-FU);

[0031] Figure 2 This is a diagram showing the effect of the Chinese medicine composition of the present invention on the tumor volume and body weight of 4T1 tumor-bearing mice. DETAILED DESCRIPTION

[0032] In order to enable those skilled in the art to better understand the technical solutions in the embodiments of the present invention and to make the above-mentioned objects, features and advantages of the present invention more obvious and understandable, the specific implementation modes of the present invention are further described below.

[0033] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0034] A multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression, comprising the following components by weight:

[0035] 25-35 parts of jujube, 18-25 parts of Millettia reticulata, 6-15 parts of Psoralea corylifolia, 6-15 parts of Ligustrum lucidum fruit, and 10-20 parts of Acanthopanax senticosus.

[0036] The properties, flavors, meridians and effects of each ingredient in this formula are as follows:

[0037] Jujube: sweet in taste, warm in nature, enters the spleen, stomach, and heart meridians. It has the effects of nourishing the middle qi, nourishing blood, and calming the mind.

[0038] Acanthopanax: Spicy, slightly bitter, warm in nature, enters the spleen, lung, heart and kidney meridians. It has the effects of replenishing the qi of the heart and spleen, nourishing qi and blood, calming the mind and improving the will. It is mainly used for spleen deficiency and fatigue, kidney deficiency and soreness of waist and knees, palpitations and insomnia, chest pain and heartache.

[0039] Millettia reticulata: bitter and sweet in taste, warm in nature, enters the liver and kidney meridians, has the effects of promoting blood circulation and replenishing blood, regulating menstruation and relieving pain, relaxing meridians and activating collaterals, and is mainly used for rheumatic pain, numbness and paralysis, and blood deficiency and sallow complexion.

[0040] Psoralea corylifolia: It tastes pungent and bitter, is warm in nature, and belongs to the spleen and kidney meridians. It has the functions of tonifying the kidney and strengthening yang, consolidating semen and reducing urine, and promoting qi and relieving asthma. It is mainly used for impotence due to kidney deficiency, warming the spleen and stopping diarrhea, and asthma due to kidney deficiency.

[0041] Fructus Ligustri Lucidi: Sweet and bitter in taste, cool in nature, enters the liver and kidney meridians, has the effect of nourishing the yin of the liver and kidney, nourishing blood and softening the liver. Mainly used for dizziness, insomnia, palpitations and fatigue caused by liver and kidney yin deficiency.

[0042] The multi-dimensional Chinese medicine composition for preventing myelosuppression of the present invention is described in detail below through specific examples.

[0043] Example 1

[0044] A multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression, comprising the following components by weight:

[0045] 30 parts of jujube, 20 parts of Millettia reticulata, 10 parts of Psoralea corylifolia, 10 parts of Ligustrum lucidum, and 15 parts of Acanthopanax senticosus.

[0046] The multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression of this embodiment can be boiled in an appropriate amount of water to obtain the corresponding herbal preparation.

[0047] Example 2: Multidimensional Chinese medicine composition for preventing myelosuppression is used to prevent myelosuppression caused by 5-fluorouracil (5-FU)

[0048] Chemotherapy usually causes bone marrow suppression, and the degree of bone marrow suppression caused by different chemotherapy drugs varies. Among them, studies have shown that high doses of 5-FU can cause strong bone marrow suppression. Therefore, this experiment selected 150mg / kg 5-FU to construct a bone marrow suppression model. Bone marrow suppression refers to the decrease in the activity of blood cell precursor cells in the bone marrow, which is a comprehensive effect on blood cells, mainly including the effects on platelets, red blood cells, lymphocytes, neutrophils and white blood cells.

[0049] Based on the Chinese medicine composition of Example 1, the dosage coefficient of normal adult and rat administration is converted according to the human and rat drug dosage conversion formula: 大鼠 =d 人 *(k 大鼠 / k 人 ), calculate the dosage for rats. 大鼠 , k 人 are the conversion coefficients for rats and humans, respectively. After conversion, the dosage for rats in this embodiment is as follows:

[0050] 5 parts of jujube, 3.2 parts of Millettia reticulata, 1.6 parts of Psoralea corylifolia, 1.6 parts of Ligustrum lucidum, and 2.4 parts of Acanthopanax senticosus.

[0051] The above ingredients are added into appropriate amount of water for decoction to obtain herbal preparation for animal experiment.

[0052] In the experiment, SD rats were divided into three groups: control group (Group A), 5-FU monotherapy group (Group B) and 5-FU + Chinese medicine combination group (Group C), with four rats in each group. Group C was administered with the above-mentioned herbal preparation by gavage at a dose of 20 ml / kg. Groups A and B were gavaged with an equal amount of normal saline. Daily gavage began two weeks before the administration of 5-FU, and gavage was performed again one hour before the administration of 5-FU, and this day was recorded as Day 0. Starting from the 6th day, blood was collected from the rats' orbits every two days, and the absolute counts and statistical analyses of five types of blood cells, including platelets, red blood cells, white blood cells, neutrophils, and lymphocytes, were performed. The statistical analysis results are shown below. Figure 1 shown.

[0053] Depend on Figure 1 It can be seen that compared with the Control group, all types of blood cells in the 5-FU group were significantly reduced, proving that the bone marrow suppression model was successfully constructed. Among them, platelets showed significant differences in the combined medication group (Group C) from the eighth day compared with the 5-FU monotherapy group (Group B); red blood cells showed significant differences from the tenth day; for neutrophils, lymphocytes and white blood cells, the significant difference was the largest on the tenth day. Based on the above data analysis, it can be seen that the multi-dimensional Chinese medicine composition for preventing bone marrow suppression of the present invention can comprehensively improve blood cell levels and prevent bone marrow suppression caused by chemotherapy.

[0054] Example 3: Effect of a multi-dimensional Chinese medicine composition for preventing bone marrow suppression on tumor volume and body weight of 4T1 tumor-bearing mice (safety experiment)

[0055] In this embodiment, based on the Chinese medicine composition of Example 1, the dosage coefficient of normal adult and mouse administration is converted according to the human and mouse drug dosage conversion formula: 小鼠 =d 人 *(k 小鼠 / k人 ), calculate the dosage for mice. 小鼠 , k 人 are the conversion coefficients for mice and humans, respectively. After conversion, the dosage for mice in this embodiment is as follows:

[0056] 3.3 parts of jujube, 2.2 parts of Millettia reticulata, 1.1 parts of Psoralea corylifolia, 1.1 parts of Ligustrum lucidum, and 1.7 parts of Acanthopanax senticosus.

[0057] The above ingredients are added into appropriate amount of water for decoction to obtain herbal preparation for animal experiment.

[0058] 4T1 cells were inoculated subcutaneously in Balb / c mice. When the subcutaneous tumor volume grew to 150 mm 3 At the same time, the mice were randomly divided into 2 groups: PBS group (group D) and Chinese medicine composition group (group E), with seven mice in each group. The Chinese medicine composition was administered as follows: 0.5ml / 10g, intragastrically every day, and the PBS group was intragastrically administered with an equal amount of normal saline. The condition of the mice was observed every other day, and the long and short diameters of the mouse tumors were measured with a vernier caliper, and the weight of the mice was recorded on a balance (average value was taken), and the total observation was 10 days. The drug safety was evaluated by calculating the mouse tumor volume and measuring the changes in mouse weight.

[0059] Tumor volume was calculated using the following formula:

[0060] The formula for calculating the mouse tumor volume is: V = (a × b 2 ) / 2

[0061] Where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0062] Observation results such as Figure 2 As shown by Figure 2 a The weight change curve of mice shows that there is no significant decrease in the weight of mice in the PBS group and the Chinese medicine combination group; Figure 2 b The change curve of mouse tumor volume shows that there is no significant difference in the change of tumor volume in the Chinese medicine composition group compared with the PBS group. This shows that the Chinese medicine composition of the present invention has low toxicity and side effects and has no obvious effect of promoting tumor growth.

[0063] Example 4: Clinical observation on the effect of a multi-dimensional Chinese medicine composition for preventing myelosuppression in preventing myelosuppression caused by TP chemotherapy

[0064] Research subjects: 20 patients who were treated with TP regimen (paclitaxel + cisplatin) for lung cancer were selected as research subjects, aged 35-70 years old, with general condition score KPS>60 points, expected survival time>3 months, no serious diseases such as heart, liver, and kidney dysfunction; no blood system diseases; no obvious abnormalities in blood routine, blood biochemistry, liver and kidney function, and no obvious abnormalities in electrocardiogram examination, excluding chemotherapy contraindications;

[0065] All patients underwent two cycles of chemotherapy: cycle A: chemotherapy alone group, who did not take the Chinese medicine composition; cycle B: chemotherapy combined with Chinese medicine composition group, who took the Chinese medicine composition 2 weeks in advance, followed by chemotherapy, and continued to take the Chinese medicine composition for 1 week during chemotherapy, for a total of 21 days of taking the Chinese medicine composition.

[0066] Blood routine test time: the day of chemotherapy start (recorded as day 1), day 7 after chemotherapy. Compare the white blood cell, neutrophil, hemoglobin concentration, and platelet values ​​after two cycles of chemotherapy A and B.

[0067] The dosage of the Chinese medicine composition used for patients in this example is as follows:

[0068] 30 parts of jujube, 20 parts of Millettia reticulata, 10 parts of Psoralea corylifolia, 10 parts of Ligustrum lucidum, and 15 parts of Acanthopanax senticosus.

[0069] Specific implementation plan:

[0070] 1. All patients undergo cycle A first, then cycle B;

[0071] 2. The day when chemotherapy starts in cycle A is recorded as day 1. Blood routine test is performed on day 1. Chemotherapy starts after contraindications are excluded. Chemotherapy ends on the same day. Blood routine test is performed again on day 7 after chemotherapy ends. After blood is drawn, the patient starts taking the Chinese medicine composition and enters cycle B;

[0072] 3. After taking the Chinese medicine composition for 2 weeks, check the blood routine, and after excluding contraindications, perform cycle B chemotherapy, and continue to take the Chinese medicine composition. After the end of cycle B chemotherapy, check the blood routine again on the 7th day;

[0073] 4. Compare the blood routine test results on the 7th day after the two cycles of chemotherapy. Verify the effect of the Chinese medicine composition in preventing and treating bone marrow suppression. See Table 1 for data:

[0074] Table 1: Comparison of white blood cell, neutrophil, platelet and hemoglobin concentrations after chemotherapy in cycles A and B

[0075]

[0076]

[0077] It can be seen from the data in Table 1 that the concentrations of white blood cells, neutrophils, platelets and hemoglobin in cycle B after chemotherapy were significantly higher than those in cycle A, and there were very significant differences between the two groups (P < 0.01), indicating that the Chinese medicine composition of the present invention can effectively prevent and treat bone marrow suppression in multiple dimensions.

[0078] It should be noted that the multidimensional herbal preparation for preventing and treating bone marrow suppression of the present invention can be made into decoctions, syrups, granules, capsules, tablets, powders, pills, oral liquids, and suspensions in addition to decoctions. In specific applications, the herbal preparation can be added to food or health products as an effective additive, such as but not limited to protein supplements or enteral nutrition. In the process of making other dosage forms, a certain amount of pharmaceutically acceptable excipient ingredients such as starch, dextrin, lactose, etc. can be added.

[0079] The embodiments of the present invention are described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions and variations made to these embodiments without departing from the principles and spirit of the present invention are still within the protection scope of the present invention.

Claims

1. A multi-dimensional Chinese medicine composition for preventing and treating bone marrow suppression, characterized in that: Contains the following ingredients by weight: 25-35 parts of jujube, 18-25 parts of Millettia reticulata, 6-15 parts of Psoralea corylifolia, 6-15 parts of Ligustrum lucidum fruit, and 10-20 parts of Acanthopanax senticosus.

2. The multidimensional Chinese medicine composition for preventing and treating bone marrow depression according to claim 1, characterized in that: The composition comprises the following components by weight: 30 parts of jujube, 20 parts of Millettia reticulata, 10 parts of Psoralea corylifolia, 10 parts of Ligustrum lucidum, and 15 parts of Acanthopanax senticosus.

3. A multi-dimensional herbal preparation for preventing and treating bone marrow suppression, characterized in that: The invention comprises active pharmaceutical ingredients, wherein the active pharmaceutical ingredients are prepared from the traditional Chinese medicine composition according to claim 1 or 2.

4. The multidimensional herbal preparation for preventing and treating bone marrow suppression according to claim 3, characterized in that: Pharmaceutically acceptable excipients are also included.

5. The multidimensional herbal preparation for preventing and treating bone marrow suppression according to claim 3 or 4, characterized in that: The herbal preparation is a decoction, a syrup, a granule, a capsule, a tablet, a decoction, a powder, a pill, an oral liquid, or a suspension.

6. The multidimensional herbal preparation for preventing and treating bone marrow suppression according to claim 5, characterized in that: The herbal preparation is added into food or health products as an effective additive.

7. Use of the multidimensional Chinese medicine composition for preventing and treating myelosuppression as claimed in claim 1 in the preparation of myelosuppression drugs.

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