HUT74576A - Method for preparing medical preparatives of bone marrow protecting and antineoplastic effects - Google Patents

Abstract

A medicament having an anti-neoplastic effect and a bone marrow protective effect by stimulation of leukocyte proliferation eliminates the detrimental effects of the administration of cytostatic drugs to or irradiation of cancer patients. A medicament of this type contains at least one or several metabolic products extracted from E. coli cultures as a bactery- and protein-free filtrate. In a preferred embodiment, a medicament of this type additionally contains an extract of ginkgo-biloba leaves. The medicament contains the active substances as a kit, combined so as to be administered at the same time, separately or successively, if necessary with a cytostatic agent.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition capable of exerting a bone marrow protective effect by stimulating white blood cell proliferation, to a pharmaceutical composition comprising a medicament, to a kit, and to a method for stimulating white blood cell proliferation and inhibiting tumor activity.

The treatment of cancer patients is still essentially performed by surgery, irradiation, hormone interventions in endocrine tumors, immune response enhancers and / or cytostatic / cell proliferation inhibitors. However, it has been found that the patient's mental and physical well-being is significantly impaired, especially when exposed to radiation and cytostatic agents. In addition, there are a number of partially dangerous side effects resulting from the general inhibition of rapidly proliferating and rapidly regenerating tissues. Such a system is also known as the hematopoietic system, which is known to be particularly damaged by irradiation and / or cytostatic treatment. Accordingly, leukocytopenia may occur in patients who have received cytostatic or radiation therapy during chemotherapy, which may lead to severe anemia through thrombocytopenia. Therefore, cytostatic drug should not be used in infinitely high doses during chemotherapy. It is an object of the present invention to overcome these disadvantages.

It is known that cultures of Escherichia coli ·· «

- 3 bacteria and a protein-free metabolite filtrate can be recovered. Such a filtrate can be prepared, for example, by culturing E. coli bacteria for 5 days. After killing the bacteria, the metabolites can be removed by filtration. After filtration, the extract contains non-pyrogenic metabolites.

Such a product, already known as Colibiogen, is marketed as a medicament by Laves-Arzneimittel GmbH Ronnenberg / Hannover in Germany, both as an oral solution and as a solution for injection. For example, an ampoule for injection contains 2 ml of a protein-free solution of 4 trillion E. coli-derived metabolites.

These pharmaceutical indications include organic functional bowel disease origin and r, which are above all I spastic disorders little worth, and Crohn's disease, ulcerative colitis j, urticaria, eczema, purpura, food ^allergy,! lung asthma, spastic bronchitis, acne and migraines. Indications for oral use include intestinal motility and gastrointestinal permeability, intestinal mucosal damage, intestinal flora damage following chemotherapy and antibiotic therapy, gastrointestinal intestinal rut, endogenous enzyme, chronic anorexia and intestinal cramps. When analyzing such a filtrate, it is essentially a

- 4 polysaccharide moieties are mainly composed of glucose, galactose and xylose. The filtrate also contains peptide components consisting essentially of asparagine, glutamic acid, alanine, glycine, lysine, leucine. Small amounts of fatty acids can also be detected, mainly palmitic and stearic oleic acids. Finally, there is little in the filtered solution of the E. coli extract

3-Hydroxy-myristic acid and small amounts of bacterial endotoxin are also present.

Surprisingly, it has now been found that the above stated goal, which is to stimulate leukocyte proliferation and thereby protect the bone marrow, in particular by irradiation and / or cytostatic therapy, can be achieved by using at least one or possibly several coliobacterial metabolites which E. coli cultures can be obtained in bacterial and protein-free filtrates.

Preferably, however, more such metabolites or whole filtrates are used. It has surprisingly been found that said metabolites of this filtrate also have antitumor activity.

Therefore, the present invention provides a pharmaceutical composition according to the above new indications, which uses a metabolic product of a bacterial and protein-free filtrate obtained from E. coli cultures. Such a method is particularly useful in the treatment of cancer patients with cytostatic chemotherapy. It is also effective for radiation therapy • 44 · ·· • 4 · · 4. Preferably, the medicament of the present invention is administered separately from the cytostatic agent, at the same time or at the same time. It is particularly preferred that the medicament be administered once or repeatedly prior to administration of the cytostatic agent. However, both single administration prior to the start of cytostatic chemotherapy and prior to the administration of certain cytostatic applications have proved to be expedient.

The patient is usually pretreated with at least one of the pharmaceutical formulations for 2 hours to 5 minutes, preferably 1 to 0.5 hours, prior to administration of the cytostatic agent or irradiation, but preferably both medications are used. Even if pre-treatment is performed 1-2 days before radiation and / or chemotherapy, good results can still be obtained. The surprising effect underlying the invention can also be demonstrated with continuous oral administration.

Surprisingly, it has been found that the protective effect underlying the invention is achievable with all known chemical cytostatic agents. However, the combination with the pharmaceutical composition of the present invention should be selected under standard conditions known to the physician, having regard to the type of tumor. Preferred cytostatic agents for colon and stomach cancers are Fluorouracil, breast cancers are Fluorouracil, Cyclophosphamid, Epirubicin, Methotrexat, and squamous cell cancers are Vepesid and Platinex. Of the above tumor types, the medicament of the present invention is particularly effective in squamous cell carcinoma.

When using a combination of a cytostatic agent and a medicament produced in accordance with the invention, it has surprisingly been found that the reduction in white blood cell count caused by cytostatic treatment is not only completely reversible, but also increases in white blood cell count compared to the baseline. Thus, the medicament according to the invention is particularly suitable for the treatment of tumors that have been previously treated with cytostatic chemotherapy and which otherwise have a very adverse reaction to the treatment. The medicament according to the invention is therefore particularly suitable for metastatic tumors.

According to the present invention, it has also been found that the antitumor activity described above is surprisingly potentiated by the use of bacterial and protein-free filtrates and ginkgo biloba leaf extracts containing E. coli metabolites. The invention therefore also relates to a pharmaceutical composition which is a compound of formula Ξ. coli is a combination of bacterial and protein-free filtrate and ginkgo biloba leaf extract. The preparation of such extracts is known and commercially available from various manufacturers. For example, Dr. Willmar Schwabe, Karlsruhe, Germany, sells a standardized extract of ginkgo flavon glycoside in the form of drops, drops and infusion ampoules under the trade name Tebonin. Indications for malnutrition and malnutrition are cerebral and peripheral haemorrhages as an indication of this natural substance, and certain symptoms of brain power weakness such as dizziness, tinnitus and, above all, vascular headaches and visual disturbances can be corrected. In vascular-related hearing, the ear improves hearing and speech impairment. In addition, attention and concentration, intellectual performance, anxiety and depression depression, and neurological disorders are also improved.

In accordance with the present invention, it has now been found that the antitumor effect achieved by a combination of cytostatic agents and E. coli metabolites is further enhanced by the addition of a substance derived from ginkgo biloba leaf extract. After the additional administration of such an extract, even tumors and metastases which have not previously responded to any drug or other pharmaceutical form are in remission. An increased effect can also be observed with radiation treatment.

The invention therefore also relates to a pharmaceutical composition comprising a bacterial and protein-free filtrate of metabolites of E. coli and an extract of ginkgo biloba leaf. According to the present invention, the pharmaceutical composition may contain E. coli metabolites and ginkgo biloba leaf extract as a spatially separate formulation for simultaneous, separate or time-shared use. THE ··"

The 8 pharmaceutical compositions of the present invention preferably contain ginkgo leaf extract in a standardized form for ginkgo flavon glycosides. Preferably, the filtrate containing the E. coli metabolites and / or the ginkgo leaf extract is in intravenous administration and is preferably an infusion and / or injection ampoule. Continuous oral administration of ginkgo extract and E. coli filtrate also achieves the effect of the present invention.

In a particularly preferred embodiment, the pharmaceutical composition of the invention further comprises a cytostatic drug in a spaced-apart form for simultaneous, separated or temporally dispersed use.

Preferably, the pharmaceutical composition of the invention is administered as a pretreatment prior to irradiation and / or cytostatic administration. Preferably, it is useful for the treatment of cancerous diseases, in particular for the treatment of breast cancer, prostate cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, sarcoma, gallbladder, esophageal cancer or melanoma.

The invention is illustrated by the following examples.

Example 1

18 patients with metastatic breast cancer receive 200 mg of ginkgo extract as a pre-infusion (Tebonin, Schwabe, Karlsruhe, Germany) prior to commencing cytostatic chemotherapy with Fluorouracil.

··· ··· · · «« · ·· ····

Before each administration of Fluorouracil, 2 ml of a protein-free solution containing 4 trillion E. coli metabolites is administered daily. The treatment is continued for 5 days, during which the ginkgo extract and the E. coli filtrate are administered intravenously each time prior to cytostatic administration. Additionally, many patients receive additional low-dose cytostatic drugs, such as Platinex, Vepeside, Cyclophosphamide, Methotrexat and Epirubicin. Remarkably, all 18 breast cancer patients had remission of metastases, although these patients had been previously failed several times with cytostatic chemotherapy.

Example 2

As described in Example 1, additional patients with gastric cancer, oesophageal cancer and squamous cell carcinoma who had not responded to any therapy were treated successfully with a combination of ginkgo extract, E. coli filtrate and cytostatic agent. In each case, a pronounced remission was achieved with the use of the drug combination of the invention.

Claims (21)

Claims CLAIMS 1. A process for the preparation of a medicament for inducing bone marrow proliferation and / or antitumor activity, comprising at least one metabolic product obtainable from bacterial and protein-free filtrates from Sscherichia coli cultures. A process for the preparation of a medicament for use in the cytostatic chemotherapy of cancer patients according to claim 1. A process for the preparation of a medicament according to claim 1 or 2, characterized in that it is used as a pretreatment during cytostatic chemotherapy. 4. A kit according to any one of claims 1-3. A medicament prepared according to any one of claims 1 to 4 in the form of a combined preparation which is administered simultaneously, separately or in time, with a cytostatic agent. 5. A pharmaceutical composition comprising a combination of at least one metabolite and ginkgobiloba leaf extract obtained from E. coli culture as a bacterial and protein-free filtrate. Pharmaceutical composition according to claim 5, characterized in that it contains the metabolites and the ginkgo leaf extract in admixture. Pharmaceutical composition according to claim 5, characterized in that the metabolites produced from E. coli and ginkgo leaf extract are spatially separated for simultaneous, separate or time-shared use. Pharmaceutical composition according to any one of claims 5 to 7, characterized in that it contains a standardized extract of ginkgo flavonglycosides. 9. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains metabolites derived from E. coli and / or ginkgo leaf extract in intravenous form. 10. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains metabolites derived from E. coli and ginkgo leaf extract in the form of an infusion and / or injection ampoule. 11. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it comprises a cytostatic drug in a spatially separate form for simultaneous, separate or temporally dispersed use. 12. A process for the preparation of a medicament having a bone marrow protective and / or antitumour activity by stimulating white blood cell proliferation, characterized in that: "9 9 9 9 999 9 99 • e · · · · * 99 99 that you are using one or more metabolic products which E. coli cultures can be recovered as bacterial and protein-free filtrates. 13. The method of claim 11, wherein: 1 for use in radiation and / or cytostatic therapy to protect the bone marrow. 14. The method of claim 13, wherein: It is contemplated that metabolites derived from E. coli are pretreated prior to irradiation and / or use of a cytostatic agent. 15. A 12-14. A process according to any one of claims 1 to 4, characterized in that Ξ. coli-derived metabolites are used to treat cancer. 16. The method of claim 15, wherein: A cancer disease is selected from the group consisting of breast cancer, prostate cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, sarcoma, gallbladder cancer, colon cancer or melanoma. 17. The method of claim 15 or 16, wherein the cancer is a metastatic cancer. 18. A 12-17. A process according to any one of claims 1 to 3, characterized in that it is primarily ginkgo. biloba leaf extract is administered. 19. A · 12-18. Any of claims 1 to 5 9 9 * * · * · · · «· • · * · · - 13 passages characterized by intravenous administration of E. coli-derived products and / or ginkgo leaf extract. 20. The method of claim 19, wherein: It is contemplated that E. coli-derived products and ginkgo leaf extract are administered separately by infusion and / or injection. 21. A method according to any one of claims 1 to 6, characterized in that the ginkgo leaf extract is applied as a single pretreatment before the start of radiation and / or cytostatic treatment. The agent shall: ·· Λ9 · Λ * · * ♦ · * · · «· · · · · · 14 Claims Use of a bacterial and protein-free filtrate from cultures of Escherichia coli for the preparation of a medicament for stimulating white blood cell proliferation. Use according to claim 1 for the manufacture of a medicament for the protection of bone marrow. Use according to claim 1 for the preparation of a medicament having anticancer activity. 4. Use according to any one of claims 1 to 3, characterized in that the medicament to be manufactured is formulated with respect to the chemotherapy of cancer patients. 5. Use according to any one of claims 1 to 3, characterized in that the medicament to be prepared is formulated as a pretreatment agent for cytostatic chemotherapy. Use of a bacterial and protein-free filtrate obtained from Escherichia coli cultures together with a ginkgo leaf extract for the preparation of a medicament for stimulating leukocyte proliferation. 7. A pharmaceutical composition comprising a combination of at least one metabolite and ginkgo biloba leaf extract obtained from bacterial and protein-free filtrates from E. coli cultures. Pharmaceutical composition according to claim 7, characterized in that it contains a standardized extract of ginkgo flavon glycosides. The pharmaceutical composition according to claim 7 or 8, for intravenous administration. 10. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it comprises, in a spatially separated form, a cytostatic agent for simultaneous, separate or time-dispersed use.