WO2009074065A1 - Utilisation de daphné primeverosyl genkwanine et de plantes de daphné - Google Patents
Utilisation de daphné primeverosyl genkwanine et de plantes de daphné Download PDFInfo
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- WO2009074065A1 WO2009074065A1 PCT/CN2008/073216 CN2008073216W WO2009074065A1 WO 2009074065 A1 WO2009074065 A1 WO 2009074065A1 CN 2008073216 W CN2008073216 W CN 2008073216W WO 2009074065 A1 WO2009074065 A1 WO 2009074065A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/83—Thymelaeaceae (Mezereum family), e.g. leatherwood or false ohelo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the invention relates to the field of botanical drugs. More specifically, it relates to the use of the genus Durian and the Daphnepr imeverosyl-Genkwanine (DPG) extracted from the genus Durian. Background technique
- the treatment level of leukemia has also been greatly improved. People are not only satisfied with the complete remission of patients, but also committed to the study of patients who have long-term disease-free survival and even recovery.
- the treatment of leukemia is chemotherapy. , integrated Chinese and Western medicine treatment, and hematopoietic stem cell transplantation.
- Chemotherapy uses chemical agents to kill leukemia cells, so that patients can achieve long-term survival and even cure. There are many types of leukemia, and different chemotherapy regimens should be chosen for different leukemia types. At present, the success rate of chemotherapy is low. The cause of failure is early death due to infection and bleeding during chemotherapy, or leukemia cells are resistant and have no effect.
- Hematopoietic stem cell transplantation is arguably the most fundamental method of treating leukemia. However, it has great risks. There are two main points: First, there are many transplant-related complications in HSCT, and second, there is still leukemia recurrence after HSCT: The main transplant-related complications are: Hepatic vein occlusion, its incidence 25%, mortality rate is 80%, graft versus host disease, incidence rate is 10%-80%. The recurrence rate of leukemia after HSCT is about 15%-50%.
- the present invention is intended to provide a compound of formula I, or a plant extract containing a compound of formula I, or a novel use of a prodrug containing a compound of formula I.
- a second object of the invention is to provide a pharmaceutical composition.
- a third object of the invention is to provide a method of treating leukemia.
- a fragrant primrose-baicalin as shown in Formula I (Daphne primeverosyl-Genkwanine, DPG), or an alcoholic extract of the genus Raytheon of the scent of scented scented scutellaria, as shown in Formula I, or a scented scented sage
- DPG Diphne primeverosyl-Genkwanine
- the leukemia is selected from the group consisting of drug-resistant acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome (MDS), or end stage multiple myeloma (Kahler's disease).
- the genus genus is selected from the group consisting of Phnom Penh scent (/3 ⁇ 4p/7/j e odora Thunb), Tcit (Daphne genkwa Sieb. et Zucc), and white scent (Z?ap?/je papyracea Wall, Ex Steud), Cloud Daphne y arwnsis H F. Zhou); More preferably, the whole grass powder of the genus Durian.
- the alcohol extract is selected from the group consisting of methanol or ethanol extract.
- the alcohol extract is obtained by the following steps:
- step (a) the method further comprises the steps of:
- the medicament is a dosage form selected from the group consisting of an oral capsule, a powder, a tablet, an elixir, a patch, a plaster, a soup, an injection, a sustained release, a medicinal liquor, or an oral solution.
- a pharmaceutical composition comprising - (i) as a living ingredient, a fragrant primrose flavonoid as shown in formula I
- DPG Dermataryosyl-Genkwanine
- the active ingredient has a weight of from 1 to 99% by weight based on the total weight of the composition.
- the genus of the genus genus is selected from the group consisting of Z3 ⁇ 4p?/7e odora Thunb, the flower (Z3 ⁇ 4pA/?e genkwaSieb. et Zucc), and the Zfep we papyracea Wall (ex Steud) , or Dap/me yunnar nsis HF Zhou;
- the alcohol extract is selected from the group consisting of methanol or ethanol extract.
- a method of preparing a medicament for treating leukemia comprising the steps of: administering Daphne prime verosyl-Genkwanine (DPG) as shown in Formula I, or An alcoholic extract of a genus of the genus eucalyptus containing the scented scent of scented scutellaria as shown in Formula I, or a medicinal material of medicinal medicinal material containing ruthenium scutellaria and scutellarin as shown in Formula I Acceptable carriers are obtained by mixing.
- DPG Daphne prime verosyl-Genkwanine
- a method of treating leukemia which comprises administering to a patient a Daphnepr imeverosyl-Genkwanine (DPG) as shown in Formula I, or An alcoholic extract of the genus Durian of the scented scented scutellaria- safflorin as shown in Formula I, or a medicinal material of the genus eucalyptus containing the scented sage of the formula I.
- DPG Daphnepr imeverosyl-Genkwanine
- An alcoholic extract of the genus Durian of the scented scented scutellaria- safflorin as shown in Formula I
- a medicinal material of the genus eucalyptus containing the scented sage of the formula I.
- Figure 1 shows the condition of the L1210 mouse leukemia cell line.
- FIG 2 shows the effect of DPG on the L 1210 mouse leukemia cell line.
- Replacement page Article 26
- Figure 3 shows the condition of human embryonic normal fibroblasts (HLF).
- FIG. 4 shows the effect of DPG on human embryonic normal fibroblasts (HLF).
- the inventors After extensive and intensive research, the inventors have unexpectedly discovered that the whole plant of the genus Durian has a pathological positive effect on human malignant hematological diseases. Further, the inventors have found that a compound of the formula I (5-0- ⁇ -OH- primrose- safflorin, Daphne priraeverosyl-Genkwanine, DPG) can be extracted from the above-mentioned genus Durian. It has obvious anti-proliferative and pro-apoptotic effects on leukemia cells and can inhibit the growth of leukemia cells.
- a compound of the formula I 5-0- ⁇ -OH- primrose- safflorin, Daphne priraeverosyl-Genkwanine, DPG
- whole grass refers to the whole grass of the genus Durian, including the roots, stems, branches, and leaves of the plant, and the genus Daphne odora Thunb), Daphne genkwa Sieb. et Zucc) , Daphne papyracea Wall, ex Steud, or Z3 ⁇ 4pj3 ⁇ 4/7e yunnanensis HF Zhou.
- whole grass powder or “whole grass powder” is used interchangeably to mean that after drying the whole plant of the genus Durian, it is pulverized into 50-200 mesh particles, preferably 70-150 mesh, more preferably 90. - 120 mesh.
- the " Russian medicinal material” may be a whole plant of the genus Durian, or may be a part of the plant, such as roots, stems, branches, leaves, flowers, and/or fruits.
- the Durian plant whole grass powder provided by the invention can be used for treating leukemia, and the method is as follows: oral administration 3 times per dose, 2 doses / 50 kg body weight per dose, 1 gram per dose, 6 grams per day. The doctor can make adjustments according to the disease and the specific conditions of the patient.
- the present invention provides an extract of the genus Durian, the extract being selected from the group consisting of methanol or ethanol extraction.
- the alcohol extract and/or DPG provided by the present invention can be used for the treatment of leukemia by using 3 times a day, 2 doses per 50 kg body weight, 10 mg alcohol extract or DPG per dose, and a total daily dose of 60 mg.
- the doctor can make adjustments according to the disease and the specific circumstances of the patient.
- the leukemias treated by the present invention include drug-resistant acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and end-stage multiple myeloma (Kahler's dise ase ).
- the natural genus of the genus Rutaceae belongs to the genus Rutaceae, about 70 species, distributed in the temperate and subtropical regions of Europe, North Africa and Asia to Oceania. There are 35 species in China, most of which are in the southwest and northwest. Rarely, some types of bast fiber are the raw materials for papermaking, and some are for viewing.
- the method for treating leukemia provided by the present invention can be reversed to prolong or prevent the recurrence of leukemia
- the method for treating leukemia provided by the invention can prevent multidrug resistance of leukemia
- the method for treating leukemia provided by the present invention has small toxic and side effects.
- the method for treating multiple myeloma provided by the invention can not only induce remission, but also has obvious analgesic effect.
- the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
- the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, Otherwise all percentages and parts are by weight.
- Standard DPG was purchased from SIGMA, and DPG refined products extracted from four different species of the same genus of scented plants, i.e., DPG (No. 1-4) obtained in Examples 9-12, were subjected to thin plate chromatography analysis.
- the chromatographic spots were found to be singular, and the migration position was consistent with the control, and the molecular weight was completely consistent with the control.
- Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature is exactly the same.
- Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature is exactly the same.
- Example 14 The standard and four different species of DPG extracts extracted from the genus of the same genus, that is, the DPG (No. 1-4) obtained in Example 9-12, are fine needle-like crystal powders. , insoluble in ether, chloroform or water, but soluble in methanol or ethanol. The nature
- the whole grass powder I prepared in Example 1 was used to treat refractory and relapsed acute leukemia in 3 cases (ALL2 cases, AGL1 cases) (volunteers), 1 case of AGL was partially relieved; 1 case of ALL improved, 1 case of ALL invalid.
- Ruixiang whole grass powder has been shown to have a pathological positive effect on human hematological malignancies, and has anti-primary cell effect on drug-resistant acute leukemia and chronic myeloid leukemia, leukemia cells are significantly reduced, blood picture is improved, Partial or complete relief.
- the alcohol extract I prepared in Example 5 was subjected to a cell test to observe the in vitro biological effect on the L 1210 mouse leukemia cell line. It was found that alcohol extract I can significantly promote apoptosis and inhibit the growth of leukemia cells.
- Example 19 The cell assay in Example 15 was repeated using the alcohol extracts I I-IV prepared in Examples 6-8, and it was also found that the alcohol extract I I-IV had a significant pro-apoptotic effect and inhibited the growth of leukemia cells, and Normal cells have no effect.
- Example 19 The cell assay in Example 15 was repeated using the alcohol extracts I I-IV prepared in Examples 6-8, and it was also found that the alcohol extract I I-IV had a significant pro-apoptotic effect and inhibited the growth of leukemia cells, and Normal cells have no effect. Example 19
- the cell test was carried out using DPG (No. 1) prepared in Example 9, and the in vitro biological effect on the L1210 mouse leukemia cell line was observed.
- Figure 1 is a control: without DPG, cultured at 37 °C for 3 days;
- Figure 2 shows the addition of 2 ug/ml DPG and incubation at 37 °C for 3 days. It was found that DPG can significantly promote apoptosis and inhibit the growth of leukemia cells.
- DPG (No. 1) prepared in Example 9 was used to treat end-stage multiple myeloma, and myeloma cells were reduced from 37% to 4.5%.
- the method of administration is: Oral DPG (No. 1), 10 mg each time, 3 times a day, for 14 days for 1 course of treatment.
- Ig monoclonal paraprotein (M-protein) returned to normal, and the bone pain was obvious.
- M-protein monoclonal paraprotein
- Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth of leukemia, and the dosage is uniform.
- Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth of leukemia, and the dosage is uniform.
- Example 23 The DPG (No. 2-4) prepared in Examples 10-12 was repeatedly subjected to the in vitro cell test in Example 19, and the results showed that the standard and four different species but the same genus of the scented plant extract DPG refined product DPG ( No. 1 -4) has the same effect of inhibiting the growth
- DPG (No. 1) was fed a white rat at a dose of 0.5 mg/kg/day for 15 days, which also proved to be non-toxic.
- Example 27 The whole grass powders I I-IV and DPG (No. 2-4) prepared by using Examples 2-4 and Examples 10-12 were repeated for the test of Example 23, and the results were similar.
- Example 27 The whole grass powders I I-IV and DPG (No. 2-4) prepared by using Examples 2-4 and Examples 10-12 were repeated for the test of Example 23, and the results were similar.
- composition Formulation one is
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Description
瑞香樱草糖-芫花黄素和瑞香属植物的用途 技术领域
本发明涉及植物药物领域。 更具体地涉及瑞香属植物和从瑞香属植物中 提取的瑞香樱草糖-芫花黄素(Daphnepr imeverosyl-Genkwanine , DPG)的用 途。 背景技术
随着医学的发展与进步, 白血病的治疗水平也有了很大提高, 人们不仅 仅满足于病人的完全缓解, 而致力于最终使病人长期无病存活乃至痊愈的研 究, 目前白血病的治疗方法有化疗、 中西医结合治疗、 和造血干细胞移植等。
化疗是使用化学制剂杀灭白血病细胞, 使病人达到长期存活乃至治愈的 目的。 白血病的类型很多, 对不同的白血病类型应选择不同的化疗方案。 目 前,化疗的成功率较低, 失败的原因有化疗期内因感染和出血引起早期死亡, 或白血病细胞耐药而无效果。
对于中西医结合治疗, 无论是单纯中医中药治疗, 还是中西医药联合使 用, 效果都不是十分理想。
造血干细胞移植(HSCT)可以说是一个最根本的治疗白血病的方法。 但它 存在很大的风险, 主要有两点: 一是 HSCT 中存在许多移植相关并发症, 二 是 HSCT后仍有白血病复发问题: 主要的移植相关并发症有: 肝静脉闭塞病, 其发病率为 25%, 死亡率为 80%, 移植物抗宿主病, 发病率 10%-80%。 HSCT 后白血病复发率大约为 15%-50%。
因此, 本领域迫切需要提供一种可有效治疗白血病等克隆性恶性血液病 的物质和方法。 发明内容
本发明旨在提供如式 I的化合物, 或含有式 I化合物的植物提取物, 或 含有式 I化合物的原药材的新用途。
本发明的第二个目的, 是提供一种药物组合物。
本发明的第三个目的, 是提供一种治疗白血病的方法。 在本发明的第一方面, 提供了一种如式 I 所示的瑞香樱草糖-芫花黄素
(Daphne primeverosyl-Genkwanine, DPG), 或含有如式 I所示的瑞香樱草糖-芫 花黄素的瑞香属植物的醇提物, 或含有如式 I所示的瑞香樱草糖-芫花黄素的瑞 香属植物药材在制备治疗白血病的药物中的用途,
在另一优选例中, 所述的白血病选自耐药性急性白血病, 慢性粒细胞白血 病, 骨髓增生异常综合症 (MDS),或终末期多发性骨髓瘤 (Kahler's disease)。
在另一优选例中, 所述的瑞香属植物选自金边瑞香(/¾p/7/je odora Thunb) , Tcit (Daphne genkwaSieb. et Zucc) , 白瑞香 (Z?ap ?/je papyracea Wall, ex Steud), 云 Daphne y議 arwnsis H F. Zhou); 更优选瑞香属植物的全草粉末。 在另一优选例中, 所述的醇提物选自甲醇或乙醇提取物。
在另一优选例中, 所述的醇提物由下述步骤获得:
(a)将瑞香属植物全草粉末用甲醇和 /或乙醇提取获得。
在另一优选例中, 在步骤(a)后还包括步骤:
(b)将步骤(a)得到的醇提物用氯仿浸泡、 离心得到沉淀物; 和
(c)将沉淀物用水漂洗后得到醇提物。
在另一优选例中, 所述的药物为选自口服胶囊, 粉剂, 片剂, 酊剂, 贴剂, 膏剂, 汤药, 注射剂, 缓释剂, 药酒, 或口服液的剂型。 在本发明的第二方面, 提供了一种药物组合物, 它含有- (i) 作 为活性成分的如式 I 所示的瑞香樱草糖 -芫花黄素
(Daphneprimeverosyl-Genkwanine , DPG) , 或含有如式 I所示的瑞香樱草糖-芫 花黄素的瑞香属植物的醇提物, 或含有如式 I所示的瑞香樱草糖-芫花黄素的瑞 香属植物药材; 和
替换页(细则第 26条)
(i i)药学上可接受的载体。
在另一优选例中, 所述活性成分的重量为占有组合物总重量的 1-99%。
在另一优选例中, 所述的瑞香属植物选自金边瑞香(Z¾p ?/7e odora Thunb) , 完花 (Z¾pA/?e genkwaSieb. et Zucc), 白瑞香 (Zfep we papyracea Wall, ex Steud), 或云南瑞香(Dap/me yunnar nsis H. F. Zhou); 所述的醇提物选自甲醇或乙醇提取 物。 在本发明的第三方面, 提供了一种制备治疗白血病的药物的方法, 它包括 步骤: 将如式 I所示的瑞香樱草糖-芫花黄素(Daphne primeverosyl-Genkwanine, DPG) , 或含有如式 I 所示的瑞香樱草糖-芫花黄素的瑞香属植物的醇提物, 或 含有如式 I所示的瑞香樱草糖-芫花黄素的瑞香属植物药材和药学上可接受的载 体混合得到。 在本发明的第四方面, 提供了一种治疗白血病的方法, 所述的方法是对 患 者 施 用 如 式 I 所 示 的 瑞 香 樱 草 糖 - 芫 花 黄 素 (Daphnepr imeverosyl-Genkwanine , DPG), 或含有如式 I所示的瑞香樱草糖 -芫花黄素的瑞香属植物的醇提物, 或含有如式 I所示的瑞香樱草糖-芫花黄 素的瑞香属植物药材。 据此, 本发明提供了一种可有效治疗白血病等克隆性恶性血液病的物质 和方法。 附图说明
图 1显示了 L1210小鼠白血病细胞系的情况。
图 2显示了 DPG对 L 1210小鼠白血病细胞系的影响。 替换页(细则第 26条)
图 3显示了人胚正常成纤维细胞(HLF)的情况。
图 4显示了 DPG对人胚正常原纤维细胞(HLF)的影响。 具体实施方式
发明人经过广泛而深入的研究, 意外地发现瑞香属植物的全草对人类恶性 血液病有病理学上的阳性效应。 进一步地, 发明人发现可以从上述的瑞香属植 物中提取得到一种化学结构式如式 I的化合物(5-0- β -OH-樱草糖 -芫花黄素, Daphne priraeverosyl-Genkwanine , DPG), 它对白血病细胞具有明显的抗增 殖和促凋亡作用, 能够抑制白血病细胞的生长。
如本文所用, "全草" 是指瑞香属植物的全草, 包括植物的根、 茎、 枝、 叶, 所述的瑞香属植物优选金边瑞香 Daphne odora Thunb) ,芫花 Daphne genkwaSieb. e t Zucc), 白瑞香 {Daphne papyracea Wall, ex Steud), 或云 南瑞香 (Z¾pj¾/7e yunnanensis H. F. Zhou)。
如本文所用, "全草粉末" 或 "全草粉剂" 可互换使用, 是指将瑞香属 植物的全草晒干后, 粉碎成 50-200 目的颗粒物, 优选 70- 150 目, 更优选 90- 120 目。
如本文所用, 所述的 "瑞香属植物药材" 可以是瑞香属植物的全株, 也 可以是所述植物的局部, 如根、 茎、 枝、 叶、 花、 和 /或果实等。 本发明提供的瑞香属植物全草粉末可用于治疗白血病, 使用方法为每曰 口服 3次, 每次 2剂 /50kg体重, 每剂 1克,每日总量 6克。 医生可根据疾病 和病人的具体情况作相应的调整。 本发明提供瑞香属植物的提取物, 所述的提取物选自甲醇或乙醇提取
-4- 替换页(细则第 26条)
物。 可以使用本领域常规的方法获得, 一种优选的方法是在全草粉末中加入 乙醇, 回流提取、 离心后, 取乙醇萃取液, 减压抽干, 得到固体粉末。 一种 更佳的方法是在全草粉末中加入乙醇, 回流提取、 离心后, 取乙醇萃取液, 减压抽干, 得到固体粉末; 加入氯仿, 浸泡过夜, 次日离心, 弃去氯仿; 再 加入氯仿洗涤一次, 离心取沉淀物; 减压抽干氯仿, 得到固体, 用蒸馏水漂 洗两次, 烘干得到精制提取物(DPG)。
本发明提供的醇提物和 /或 DPG可用于治疗白血病, 使用方法为每日 3次, 每次 2剂 /50kg体重, 每剂 10毫克醇提物或 DPG,每日总量 60毫克。 医生可根 据疾病和病人的具体情况作相应的调整。 本发明所治疗的白血病包括耐药性急性白血病, 慢性粒细胞白血病, 骨 髓增生异常综合症和终末期多发性骨髓瘤 (Kahler's disease)。 本发明的天然瑞香属植物属瑞香科, 桃金娘目, 约 70种, 分布于欧洲、 北非和亚洲温带和亚热带地区至大洋洲, 我国有 35 种, 大部产西南部和西 北部, 他处少见, 有些种类的靭皮纤维为制纸的原料, 有些供观赏。
所属科瑞香科在我国主要品种种名如下:
尖瓣瑞香 acu tiloba Rehd.
澄黄瑞香 apAoe auran thiaca Diels
藏东瑞香 bholua Buch. -Ham. ex D. Don
fe ^ ¾ ^ Daphne bre vi tuba H. F. Zhou
7JN R† Jffii ^ Daphne championi i Ben th.
少花瑞香 apAoe depaupera ta H. F. Zhou
峨眉瑞香 Daphne emeiensis C. Y. Chang
啮蚀瓣瑞香 Daphne erosiloba C. Y. Chang
白脉瑞香 apAoe esquirol i i Le vi.
短瓣瑞香 Daphne feddei Le vi.
J 11 H ¾ ^ Daphne gemma ta E. Pri tz.
HDaphne genkwa Sieb. e t Zucc.
绢毛瑞香 Daphne holosericea (Diels) Hamaya
If ill Jffit ^ Daphne leishanensis H. F. Zhou
^ IH ¾ ^ Daphne longi loba ta (Lecomte) Turrill
大花瑞香 macran tha Ludlow
瘦叶瑞香 Daphne modes ta Rehd.
长梗瑞香 apAoe peduncula ta H. F. Zhou
紫花瑞香 apAoe purpurascens S. C. Huang
H 0† Jffit Daphne re tusa Hemsl.
口彖果瑞香 rhynchocarpa C. Y. Chang
甘青瑞香 Daphne tangutica Maxim.
细花瑞香 apAoe tenui flora Bur.
fi' ^n ^ Daphne triparti te H. F. Zhou
西畴瑞香 apAoe xichouensis H. F. Zhou
本发明优选的品种是金边瑞香 ( aphne odora Thunb),芫花 (J)aPhne genkwaSieb. e t Zucc) , ί=| ¾ ^ (Daphne papyracea Wall, ex Steud) , 或云 南瑞香 ( apAoe yunnanensis H. F. Zhou) α
本发明提到的上述特征, 或实施例提到的特征可以任意组合。 本案说明书 所揭示的所有特征可与任何组合物形式并用, 说明书中所揭示的各个特征, 可 以任何可提供相同、 均等或相似目的的替代性特征取代。 因此除有特别说明, 所揭示的特征仅为均等或相似特征的一般性例子。 本发明的主要优点在于:
1、 本发明提供的治疗白血病的方法可逆转,延长或阻止白血病的复发;
2、 本发明提供的治疗白血病的方法可防止白血病多药耐药;
3、 本发明提供的治疗白血病的方法毒副作用小。
4、 本发明所提供的治疗多发性骨髓瘤的方法,不仅可诱使取得缓解,且 止痛效果明显。 下面结合具体实施例, 进一步阐述本发明。 应理解, 这些实施例仅用于 说明本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实 验方法, 通常按照常规条件或按照制造厂商所建议的条件。 除非另外说明,
否则所有的百分比和份数按重量计。
除非另行定义, 文中所使用的所有专业与科学用语与本领域熟练人员所 熟悉的意义相同。 此外, 任何与所记载内容相似或均等的方法及材料皆可应 用于本发明方法中。 文中所述的较佳实施方法与材料仅作示范之用。 实施例 1
制备全草粉末 I
采用金边瑞香 Daphne odora Thunb ±蓴, 晒干后, 经粉碎成 100 目颗 粒物, 得到全草粉末 I。 实施例 2
制备全草粉末 II
采用芫花 ¼7 ?/76> genkwa Sieb. et Z"cc全草, 晒干后, 经粉碎成 100 目 颗粒物, 得到全草粉末 Π。 实施例 3
制备全草粉末 III
采用白瑞香 papyracea Wall, ex S e .全草, 晒干后, 经粉碎 成 100 目颗粒物, 得到全草粉末 III。 实施例 4
制备全草粉末 IV
^ 云 Daphne yu醒 sis H. F. Zhou, 晒干后, 经粉碎成 100 目颗粒物, 得到全草粉末 IV。 实施例 5
制备醇提物 I
称取 50克全草粉末 I, 加入 200毫升乙醇, 回流提取 2小时。 离心, 取 乙醇萃取液, 减压抽干, 得到固体粉末即醇提物 I。 实施例 6
制备醇提物 II
称取 50克全草粉末 I I, 加入 200毫升甲醇, 回流提取 2小时。 离心, 取甲醇萃取液, 减压抽干, 得到固体粉末即醇提物 I I。 实施例 7
制备醇提物 III
称取 50克全草粉末 I I I, 加入 200毫升甲醇, 回流提取 2小时。 离心, 取甲醇萃取液, 减压抽干, 得到固体粉末即醇提物 I I I。 实施例 8
制备醇提物 IV
称取 50克全草粉末 IV, 加入 200毫升乙醇, 回流提取 2小时。 离心, 取乙醇萃取液, 减压抽干, 得到固体粉末即醇提物 IV。 实施例 9
制备 DPG (No. 1)
称取 50克全草粉末 I, 加入 200毫升乙醇, 回流提取 2小时。 离心, 取 乙醇萃取液, 减压抽干, 得到固体粉末即醇提物 I。
加入 50毫升氯仿, 浸泡过夜。 次日离心, 弃去氯仿; 再加入 20毫升氯 仿洗涤一次, 离心取沉淀物。 减压抽干氯仿, 得到固体, 用蒸馏水漂洗两次, 烘干得到精制提取物(DPG (No. 1) )。 实施例 10
制备 DPG (No. 2)
称取 50克全草粉末 I I, 加入 200毫升甲醇, 回流提取 2小时。 离心, 取甲醇萃取液, 减压抽干, 得到固体粉末即醇提物 I I。
加入 50毫升氯仿, 浸泡过夜。 次日离心, 弃去氯仿; 再加入 20毫升氯 仿洗涤一次, 离心取沉淀物。 减压抽干氯仿, 得到固体, 用蒸馏水漂洗两次, 烘干得到精制提取物 (DPG (No. 2) )。 实施例 11
制备 DPG (No. 3)
称取 50克全草粉末 I I I, 加入 200毫升甲醇, 回流提取 2小时。 离心, 取甲醇萃取液, 减压抽干, 得到固体粉末即醇提物 I I I。
加入 50毫升氯仿, 浸泡过夜。 次日离心, 弃去氯仿; 再加入 20毫升氯 仿洗涤一次, 离心取沉淀物。 减压抽干氯仿, 得到固体, 用蒸馏水漂洗两次, 烘干得到精制提取物 (DPG (No. 3) )。 实施例 12
制备 DPG (No. 4)
称取 50克全草粉末 IV, 加入 200毫升乙醇, 回流提取 2小时。 离心, 取乙醇萃取液, 减压抽干, 得到固体粉末即醇提物 IV。
加入 50毫升氯仿, 浸泡过夜。 次日离心, 弃去氯仿; 再加入 20毫升氯 仿洗涤一次, 离心取沉淀物。 减压抽干氯仿, 得到固体, 用蒸馏水漂洗两次, 烘干得到精制提取物 (DPG (No. 3) )。 实施例 13
有效成分的鉴定
标准品 DPG购自 SIGMA, 采用从 4个不同种但同一属的瑞香植物提取的 DPG精制品, 即实施例 9-12制得的 DPG (No. 1-4), 进行薄板层析分析。
薄板层析的具体条件:
硅胶 G板, 点样后, 层析液: 正丁醇: 醋酸: 水 = 4 : 1: 1。
发现层析斑点呈单一性, 而且迁移位置与对照品一致, 分子量与对照品 完全一致。
化学性质分析: 标准品和 4个不同种但同一属的瑞香植物提取的 DPG精 制品, 即实施例 9- 12制得的 DPG (No. 1-4)对比, 均呈细粒针状结晶粉末, 不 溶于***、 氯仿或水, 但溶于甲醇或乙醇。 性质完全相同。 实施例 14
临床药理学初步观察
使用实施例 1 制得的全草粉剂 I 治疗慢性粒细胞白血病加速期患者(志 愿者) 2例, 一例无效, 另一例获部分缓解。 骨髓白血病原始细胞从 18%降至
7. 5%。 当时的给药方法是: 口服全草粉剂 I, 每次 l g, 每天 3 次, 连用 14 天为 1疗程。
用实施例 1 制得的全草粉剂 I 分别治疗难治和复发性急性白血病 3 例 (ALL2例, AGL1例)(志愿者), 内 1例 AGL获部分缓解; 1例 ALL好转, 1例 ALL无效。
结果表明, 瑞香全草粉剂已显示出对人类恶性血液病有病理学上的阳性 效应, 对耐药性急性白血病和慢性粒细胞白血病服用后有抗原始细胞效应, 白血病细胞明显减少, 血象改善, 获部分或完全缓解。
对终末期多发性骨髓瘤(Kahler' s 病)不仅可以止痛, 且血象改善, I g 单克隆副蛋白下降。 实施例 15
醇提物的效果
采用实施例 5制备的醇提取物 I进行细胞试验, 观察对 L 1210小鼠白血 病细胞系的体外生物效应。 发现醇提取物 I可明显的促凋亡作用, 能够抑制 白血病细胞的生长。
同时,还采用采用 HLF (人胚正常原纤维细胞)进行试验,发现醇提取物 I 对正常人细胞无抑制作用。 实施例 16-18
醇提物的效果
用实施例 6-8制备的醇提物 I I-IV重复实施例 15 中的细胞试验, 同样 发现醇提物 I I-IV具有明显的促凋亡作用, 能够抑制白血病细胞的生长, 且 对于正常细胞无影响。 实施例 19
DPG的作用
采用实施例 9制备的 DPG (No. 1)进行细胞试验, 观察对 L1210小鼠白血 病细胞系的体外生物效应。
其中图 1为对照: 不加 DPG, 37 °C培养 3天;
图 2为添加 2ug/ml DPG , 37 °C培养 3天。
发现 DPG可明显的促凋亡作用, 能够抑制白血病细胞的生长。
同时,还采用采用 HLF (人胚正常成纤维细胞)进行试验,发现 DPG对正常 人细胞无抑制作用(图 3, 4)。
采用实施例 9制备的 DPG (No. 1)治疗终末期多发性骨髓瘤, 骨髓瘤细胞 从 37%降至 4. 5%。 给药方法是: 口服全 DPG (No. 1), 每次 10毫克, 每天 3次, 连用 14天为 1疗程。 Ig单克隆副蛋白(M-蛋白)恢复正常, 止骨痛明显。 实施例 20-22
DPG的作用
将实施例 10-12制备的 DPG (No. 2-4)重复进行实施例 19中的体外细胞试 验, 结果表明, 标准品和 4个不同种但同一属的瑞香植物提取的 DPG精制品 DPG (No. 1 -4)具有相同的抑制白血病生长的作用, 且作用剂量一致。 实施例 23
初步毒理学研究
大白鼠亚急性毒性实验
取全草粉剂 I, 喂食白鼠, 剂量为 0. 5mg/kg/天, 连服 15天, 证明无毒 性。
DPG (No. 1 )喂食白鼠, 剂量为 0. 5mg/kg/天, 连服 15天, 同样证明无毒 性。
小白鼠急性毒性实验
取高浓度悬液(全草粉剂 1), 剂量同上, 1次给予服用, 证明无毒性。 DPG (No. 1 )喂食白鼠, 剂量为 0. 5mg/kg/天, 连服 15天, 同样证明无毒 性。
在以上大鼠实验中, 证明瑞香全草粉剂单一剂量超过临床使用的每天剂 量的数千倍也未见明显急性毒性效应。 实施例 24-26
初步毒理学研究
用实施例 2-4及实施例 10-12制备得到的全草粉剂 I I-IV和 DPG (No. 2-4) 重复实施例 23的试验, 结果类似。
实施例 27
药物组合物 配方一:
全草粉剂 I 1克
姜黄素 0.2克
赋型剂 0.3克
压成片剂制成 配方二:
醇提物 I 100毫克
姜黄素 0.2克
赋型剂 0.3克
压成片剂制成 配方三:
醇提物 ΠΙ 100毫克
青蒿素 0.2克
赋型剂 0.3克
压成片剂制成 配方四:
DPG(No.2) 10毫克
青蒿素 0.2克
赋型剂 0.3克
压成片剂制成 配方五:
DPG(No.3) 10毫克
溶解于 150微升异丙醇(助溶剂)
注射水 2毫升
过滤除菌得到注射剂 以上配方给大约 10名患有耐药性急性白血病,慢性粒细胞白血病, MDS 和 Kahler's 病的志愿者使用后, 病情都有改善。
在本发明提及的所有文献都在本申请中引用作为参考, 就如同每一篇文 献被单独引用作为参考那样。 此外应理解, 在阅读了本发明的上述讲授内容 之后, 本领域技术人员可以对本发明作各种改动或修改, 这些等价形式同样 落于本申请所附权利要求书所限定的范围。
Claims
1.一种如式 I所示的瑞香樱草糖 -芫花黄素, 或含有如式 I所示的瑞香樱草 糖-芫花黄素的瑞香属植物的醇提物, 或含有如式 I 所示的瑞香樱草糖-芫花黄 素的瑞香属植物药材在制备治疗白血病的药物中的用途,
2.如权利要求 1 所述的用途, 其特征在于, 所述的白血病选自耐药性急性 白血病, 慢性粒细胞白血病, 骨髓增生异常综合症,或终末期多发性骨髓瘤。
3.如权利要求 1所述的用途,其特征在于,所述的瑞香属植物选自金边瑞香, 芫花, 白瑞香, 或云南瑞香; 优选瑞香属植物的全草粉末。
4.如权利要求 1 所述的用途, 其特征在于, 所述的醇提物选自甲醇或乙醇 提取物。
5.如权利要求 1所述的用途, 其特征在于, 所述的醇提物由下述步骤获得:
(a)将瑞香属植物全草粉木用甲醇和 /或乙醇提取获得。
在另一优选例中, 在步骤(a)后还包括步骤:
(b)将步骤(a)得到的醇提物用氯仿浸泡、 离心得到沉淀物; 和
(c)将沉淀物用水漂洗后得到醇提物。
6.如权利要求 1 所述的用途, 其特征在于, 所述的药物为选自口服胶囊, 粉剂, 片剂, 酊剂, 贴剂, 膏剂, 汤药, 注射剂, 缓释剂, 药酒, 或口服液的 剂型。
7.—种药物组合物, 其特征在于, 它含有:
(i)作为活性成分的如式 I所示的瑞香樱草糖-芫花黄素, 或含有如式 I所 示的瑞香樱草糖-芫花黄素的瑞香属植物的醇提物, 或含有如式 I所示的瑞香樱 草糖-芫花黄素的瑞香属植物药材; 和
- 14- 替换页(细则第 26条)
(i i)药学上可接受的载体。
8.如权利要求 7 所述的药物组合物, 其特征在于, 所述活性成分的重量为 占有组合物总重量的 1-99%。
9.如权利要求 Ί 所述的药物组合物, 其特征在于, 所述的瑞香属植物选自 金边瑞香,芫花, 白瑞香, 或云南瑞香; 所述的醇提物选自甲醇或乙醇提取物。
10.—种制备治疗白血病的药物的方法, 其特征在于, 它包括步骤: 将 如式 I所示的瑞香樱草糖 -芫花黄素, 或含有如式 I所示的瑞香樱草糖 -芫花 黄素的瑞香属植物的醇提物, 或含有如式 I 所示的瑞香樱草糖-芫花黄素的 瑞香属植物药材和药学上可接受的载体混合。
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FR2597751B1 (fr) * | 1986-04-24 | 1990-10-05 | Ragot Jacqueline | Effet de synergie entre deux molecules d'origine vegetale : senegenine et 5-o-b-d-primeverosyl genkwanine utilisable dans le traitement de maladies liees a des desequilibres immunitaires |
FR2867476B1 (fr) * | 2004-03-11 | 2006-05-26 | Michel Prost | Derives de genkwanine et sakuranetine, utilisation cosmetique et therapeutique, et procede de preparation |
-
2007
- 2007-12-10 CN CN2007101719939A patent/CN101456886B/zh not_active Expired - Fee Related
-
2008
- 2008-11-27 WO PCT/CN2008/073216 patent/WO2009074065A1/zh active Application Filing
Non-Patent Citations (2)
Title |
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JI CHUNRU ET AL.: "study of flavone compounds in leaf of daphne: the structure of yuankanin", ZHONGCAOYAO(CHINESE), vol. 17, no. 11, 1986, pages 7 - 9 * |
ZHANG WEI ET AL.: "phenolic constituents from Daphne odora var. atrocaulis", NATURAL PRODUCT RESEARCH AND DEVELOPMENT(CHINESE), vol. 17, no. 1, 2005, pages 26 - 28 * |
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Publication number | Publication date |
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CN101456886A (zh) | 2009-06-17 |
CN101456886B (zh) | 2013-04-10 |
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