JPH06505016A - Method for manufacturing pharmaceutical preparations for bone marrow protective and antitumor effects - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Method for manufacturing pharmaceutical preparations for bone marrow protective and antitumor effects The present invention relates to the production of pharmaceutical preparations for obtaining bone marrow protective effects by stimulation of leukocyte proliferation; Pharmaceutical preparations containing such medicaments, as well as pharmaceutical kits and leukocyte proliferation and anti- Concerning a method of obtaining tumor action.

Currently, the treatment of tumor patients still mainly involves surgical procedures, irradiation, By treating the hormonal system in endocrine tumors, by immunostimulating agents and/or or with cytostatic chemotherapy. However, especially with irradiation and cytostatic agents, When applied, the general mental and physical condition of the patient may be significantly impaired. found. In this case, the reproduction of such tissue that proliferates or renews rapidly. A number of side effects occur, some of which are dangerous, caused by the general suppression of life. hematopoiesis lineages are also such lineages, and in the case of irradiation and/or cytostatic therapy for hematopoietic lineages. In particular, it is known to be damaged. Therefore, in the setting of chemotherapy using cytostatic agents, In patients treated with radiation therapy or radiation therapy, leukopenia occurs; Oleiasis may lead to thrombocytopenia and, in some cases, severe anemia. For this reason, In physical therapy, cytostatic agents cannot be applied in unlimited high doses. subordinate The invention therefore aims to overcome the drawbacks mentioned above.

Metabolic products from the culture of Escherichia coli It is known to produce bacteria- and protein-free filtrates of products. Such filtrate can be obtained, for example, by culturing E. coli bacteria in a medium for 5 days. Thin After eradicating the bacteria, the metabolites are extracted by filtration. Extract after filtration is pyrogenic Contains metabolites that are not present.

Such a product has the name colibiogen (ColCo11bio®). Already known as Laves-Arzneiwittel. ) from GmbH (Hannover-Ronnenberg, Germany), orally. It is sold as a medicine and as an injection solution. In this case, for example An ampoule for injection contains 2 ml of an aqueous solution of 1 trillion E. coli bacterial metabolites.

Indications for this medicine include, inter alia, organic and functional causes with spastic signs. intestinal disorders, Crohn's disease, bladder ulcers, measles, eczema, purpura, food allergies, This includes tracheal asthma, sitting pain, and migraine. For orally applied drink liquids Indications include dysmotility and intestinal mucosal permeability, chemical and antibiotic therapy. Physiological intestinal bacteria disorders, intestinal metabolism and absorption disorders, and gastrointestinal salmonella after application of the law diseases, especially in children and infants, colonic dyspepsia, endogenous enzymes, chronic anorexia and One example is Biheso Itatsutsu. During the analysis, such filtrate mainly contains It shows a polysaccharide component consisting of xylose, galactose, and xylose. Similarly, with the Lord Asparagine, glutamic acid, alanine, glycerin, lysine and leucine Also included is a peptide component containing peptides. Similarly, a small proportion of fatty acids and Among others, palmitic acid, stearic acid and oleic acid are also present. Finally, even a little A large amount of 3-hydroxymyristic acid as well as small amounts of bacterial endotoxins are also extracted from E. coli. Found in this filtered solution from the.

However, it is surprising that the above-mentioned purposes, in particular radiation therapy and/or cytostatic Stimulates leukocyte proliferation and thus has a myeloprotective effect during chemotherapeutic treatment with drugs. The purpose of the challenge was to obtain bacteria- and protein-free filtrate from E. coli cultures. This can be achieved by administering at least one or several metabolites of E. coli bacteria. It turned out that it was.

However, preferably the filtrate of some or all of these metabolites is administered. Surprisingly , it was found that the administration of such metabolites of this filtrate also formed an antitumor effect. did.

Therefore, the present invention provides bacteria and proteins containing metabolites of E. coli cultures. The present invention relates to a method for producing a medicament for the above-mentioned new indications using a non-containing filtrate. Kaka The method is recommended for application in the case of chemotherapy using cytostatic agents in cancer patients. It was very appropriate. This medicine is also effective in the case of radiotherapy. According to the present invention Medicinal products manufactured using a cytostatic agent may be manufactured in a step separate from, simultaneously with, or in time from the application of the cytostatic agent. It is preferable to use it with it on. However, if this drug is administered once or several times, the cytostatic agent It is preferable to administer the drug before the start of cytostatic chemotherapy. Both the single administration of the cytostatic agent and the administration before each individual application of the cytostatic agent have proven to be advantageous. did.

Typically, the patient is given 2 hours or 5 minutes, advantageously, before administration of the cytostatic agent or irradiation. Perform at least one preliminary administration of both pharmaceutical preparations over a period of 1 to 0.5 hours. . In particular, both medications are administered. Radiation therapy and/or chemotherapy A good effect occurs even when pre-administration is carried out 1 to 2 days before. Rather, a series In the case of continuous oral administration, the surprising effect which is the basis of the present invention is found.

Surprisingly, the protective action underlying the present invention is similar to that of all known chemical cytostatic agents. It turns out that it can be achieved. In this case, the cytostatic agent is under normal conditions known to the physician, in combination with the medicament produced according to the invention. selected. The preferred cytostatic agent for colon and gastric cancer applications is fluorocarbon Rasil, as well as fluorouracil and cyclophosphamide for breast cancer. , Epiribicin (Epirib1cin), methotrexate, Vepesid and PlatiNex for skin cancers nex). In addition to the tumor types mentioned above, the medical products produced by the present invention The drug has a good effect on squamous cell carcinoma and (.

Surprisingly, when administering a cytostatic agent in combination with a medicament produced according to the present invention, the cytostatic agent Although leukocyte suppression induced by cell therapy cannot be completely avoided, It has been found that often rather an increase in white blood cells compared to the starting state is obtained. follow Therefore, the medicament produced according to the present invention has already been used many times in cytostatic chemotherapy. It is particularly suitable for tumors that otherwise have a very inadequate response. It was true. Therefore, the medicament produced according to the invention can be used - in the treatment of metastatic tumors; It is extremely suitable for

According to the present invention, the antitumor action described above surprisingly includes metabolites of E. coli. Administer bacteria- and protein-free filtrate and extract from Ginkgo biloba leaves with It turned out that the number would increase further. Therefore, the present invention provides a method for improving the metabolism of E. coli. Extract and ginkgo biloba as bacteria- and protein-free filtrate containing the product It also relates to pharmaceutical preparations containing in combination extracts from the leaves of. Manufacture of such extracts are known and these extracts can already be purchased from various manufacturers. So, I For example, Dr. Willmar Schwabe ginkgo flavone glycosylation by Ginkgo Biloba (Karlsruhe, Germany) A highly standardized extract is available under the name Tabonin (registered trademark). , sold as dragees, drops and ampoules for injection. For this natural product preparation Indications for this include cerebral and peripheral blood perfusion deficiency and nutritional deficiencies; This can lead to symptoms of decreased brain function, such as dizziness, tinnitus, and among others (vascular condition). It can improve headaches and visual impairment. In case of inner ear hearing loss in vascular conditions, this medicine is Improve certain auditory abilities and language comprehension. In addition, memory and concentration ability, etc. and thinking abilities are improved, and anxiety and depressive disorders and neurological disorders are also improved. Improved.

By the way, according to the present invention, an antitumor drug of a combination drug of a cytostatic agent and a metabolite of E. coli The effect can be obtained by additionally administering the substances contained in the extract from ginkgo leaves. It turns out that it can be further increased. Rather, by additional administration of such extracts, This means that tumors and metastases that have not previously responded to drugs or other forms of treatment may His condition improved. Improved effects were also confirmed in the case of radiation therapy.

Therefore, the present invention provides a method for preparing filtrate from E. coli as a bacteria- and protein-free filtrate. It also relates to pharmaceutical preparations containing in combination metabolites and extracts from ginkgo leaves. Ru. According to the invention, this pharmaceutical preparation contains metabolites from E. coli and ginkgo biloba. ° to apply extracts from, simultaneously separately or in stages. , it has been found that they can be contained in mixed form as well as spatially separated. In particular, I Extracts from butterfly leaves are standardized with ginkgo flavone glycosides. contained in the pharmaceutical preparation according to the invention. In particular, it contains metabolites of E. coli. The filtrate and/or extract from ginkgo leaves can be administered intravenously. It is also advantageously present as an ampoule for injection and/or injection. Ginkgo biloba The effects of the present invention cannot be achieved even by continuous oral administration of E. coli extracts and E. coli extracts. Ru.

In a particularly preferred embodiment, the pharmaceutical preparation according to the invention can be applied separately at the same time. additionally spatially separated for application or in stages. Contains a cellulose agent.

The pharmaceutical preparation according to the invention is preferably prepared in advance of the application of radiation and/or cytostatic agents. Applied as a dosage. The preparation is particularly suitable for the treatment of tumor diseases, in particular breast cancer, Treatment of prostate cancer, stomach cancer, esophageal cancer, squamous cell carcinoma, sarcoma, bile duct cancer, colon cancer or melanoma. Suitable for medical treatment.

The invention will be explained in detail in the following.

Example 1 Eighteen patients with metastatic breast cancer received cytostatic chemotherapy with fluorouracil. Before the start, we received a text from Schwabe (Germany based in Lulsruhe). Ginkgo biloba extract 2001 available under the name Tabonin (registered trademark) 1 was ingested as the first injection. 4 trillion E before each individual fluorouracil dose. 2 ml of a protein-free solution containing metabolites of B. coli was administered per day.

Treatment lasted for 5 days, each time with ginkgo biloba extract and E. coli extract was administered by intravenous injection. Some patients may additionally receive lower doses of cytostatic agents, as well as Bratinex, Bepecid, Cyclophosphamide, and Methotrex. Ingested xate and evirivicin. At that time, all 18 women with breast cancer It was found that the patient's metastasis improved. All of these patients had He was also pretreated with cytostatic chemotherapy, but it was ineffective.

Example 2 As described in Example 1, patients with gastric cancer, esophageal cancer, or squamous cell carcinoma and Another patient who does not respond to treatment with ginkgo biloba extract, E. coli filtrate and cytostatic Treated with a combination of drugs. In all cases, administration of the pharmaceutical combination according to the invention I was able to achieve a clear sense of relief.

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Claims (21)

[Claims] 1. For myeloprotective effects by stimulation of leukocyte proliferation and/or antitumor effects In the method for producing a pharmaceutical preparation for obtaining The use of metabolites obtained as bacteria- and protein-free filtrate from A method for producing a pharmaceutical preparation for obtaining characteristic myeloprotective and antitumor effects. 2. A method for producing the medicament according to claim 1 for cytostatic chemotherapy of cancer patients. 3. A claim characterized in that it is a medicine for pre-administration in cell static chemotherapy. A method for producing a pharmaceutical according to claim 1 or 2. 4. The medicament obtained by the method of claims 1 to 3 is simultaneously administered with a cytostatic agent. Medicinal products contained as a combination preparation for application separately or in chronological stages medicine kit. 5. E. Metabolic products obtained from coli cultures as bacteria- and protein-free filtrate and an extract from ginkgo leaves in combination. Characteristics of pharmaceutical dispensing. 6. Specially contains metabolites and extracts from ginkgo leaves in mixed form. 6. A pharmaceutical preparation according to claim 5, characterized in that it has the following characteristics: 7. E. Metabolites obtained from coli and extracts from ginkgo leaves were separately or contained spatially separated for temporally staged simultaneous application. A pharmaceutical preparation according to claim 5, characterized in that: 8. Contains extract standardized by ginkgo flavone glycosides Pharmaceutical preparation according to any one of claims 5 to 7, characterized in that: 9. E. Metabolites obtained from coli and/or extracts from ginkgo leaves. Any one of claims 5 to 8, characterized in that it is contained in a form that can be administered intravenously. Pharmaceutical preparation according to item 1. 10. E. Injected with metabolites obtained from coli and extracts from ginkgo leaves. Claims 5 to 8 characterized in that it is contained as an ampoule for injection and/or as an ampule for injection. The pharmaceutical preparation according to any one of the preceding items. 11. Contains cytostatic agents for simultaneous separate or temporally staged application Pharmaceutical preparation according to any one of claims 5 to 10, characterized in that: 12. E. one obtained as a bacteria- and protein-free filtrate from a culture of E. coli or bone by stimulation of leukocyte proliferation, characterized by the use of several metabolites. A method for obtaining a medullary protective effect and/or a pile tumor effect. 13. Applied to protect bone marrow during radiotherapy and/or cytostatic therapy 12. The method according to claim 11, characterized in that: 14. E. The metabolites obtained from E. coli are treated with radiation and/or the application of cytostatic agents. 14. The method according to claim 13, characterized in that it is applied as a pre-dose beforehand. 15. E. The use of metabolites obtained from coli for the treatment of tumor diseases has been proposed. 15. A method according to any one of claims 12 to 14, characterized in that: 16. Tumor diseases include breast cancer, prostate cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, sarcoma, bile duct cancer, 16. The method according to claim 15, wherein the cancer is colon cancer or melanoma. 17. Claim 15 or 16, characterized in that the tumor disease is a metastatic tumor disease. Method described. 18. Claims characterized in that first of all an extract from ginkgo leaves is administered. 18. The method according to any one of 12 to 17. 19. E. products obtained from coli and/or extracts from ginkgo leaves. The method according to any one of claims 12 to 18, characterized in that it is administered intravenously. Law. 20. E. The product obtained from coli and the extract from ginkgo leaves were separately poured into The method according to claim 19, characterized in that the method is administered as an infusion and/or an injection solution. . 21. Extracts from ginkgo leaves can be used in radiotherapy and/or cytostatic therapy. Claims 18 to 20 characterized in that it is administered as a single predose at the beginning. The method described in any one of the above.