EP1904018A2 - Preparation combinee, en particulier pour traiter le cancer de la prostate - Google Patents

Preparation combinee, en particulier pour traiter le cancer de la prostate

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Publication number
EP1904018A2
EP1904018A2 EP06762663A EP06762663A EP1904018A2 EP 1904018 A2 EP1904018 A2 EP 1904018A2 EP 06762663 A EP06762663 A EP 06762663A EP 06762663 A EP06762663 A EP 06762663A EP 1904018 A2 EP1904018 A2 EP 1904018A2
Authority
EP
European Patent Office
Prior art keywords
prostate
inhibitor
extract
agonist
estrogen receptor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06762663A
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German (de)
English (en)
Inventor
Hubertus Jarry
Wolfgang Wuttke
Dana Seidlova-Wuttke
Michael A. Popp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bionorica Research GmbH
Original Assignee
Bionorica Research GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bionorica Research GmbH filed Critical Bionorica Research GmbH
Priority to EP06762663A priority Critical patent/EP1904018A2/fr
Publication of EP1904018A2 publication Critical patent/EP1904018A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • 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)
    • A61K36/85—Verbenaceae (Verbena family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to a composition of components for simultaneous or sequential administration or ingestion, the components comprising a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and a prostate-specific antigen inhibitor.
  • the invention also relates to the use of a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and an inhibitor of the prostate-specific antigen for the manufacture of a medicament for the prevention or treatment of a prostate disease.
  • the invention relates to the use of a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and an inhibitor of the prostate-specific antigen for the preparation of a dietary supplement for the prevention of a prostate disease.
  • an extract of Cimifuga racemosa, an extract of Vitex agnus castus or of Silybum marianum as estrogen receptor ⁇ -agonist and an extract of Belamcanda chinensis are used as 5 ⁇ -reductase inhibitor as an inhibitor of the prostate-specific antigen.
  • prostate diseases include malignant and benign prostatic hyperplasia.
  • prostatic hyperplasia prostate cancer
  • GnRH analogues or castration there are few effective alternatives to endocrine therapy by GnRH analogues or castration.
  • a relatively "organ specific" hormone ablation therapy has shown that it can significantly reduce the number of prostate cancers (PCa) that occur, ie it can be used preventively, namely the therapy with the 5 ⁇ -reductase inhibitor finasteride Blood circulating testosterone, which is produced in large quantities by the testes, into 5 ⁇ -dihydrotestosterone (5 ⁇ DHT), which is the actually effective androgen in the prostate
  • the enzyme that reduces testosterone to 5 ⁇ DHT is 5 ⁇ -reductase (cf.
  • FIG 1 This enzyme has two forms encoded on different genes: 5 ⁇ -reductase-2 is the predominantly prostate and seminal vesicle-active form, while 5 ⁇ -reductase-1 is predominantly active in hair follicles, sebaceous glands and other epithelial structures ,
  • the PSA is an enzyme which has protease activity and is able to cleave the insulin-like growth factor-1-binding protein (IGF1-BP3) in the prostate, so that IGF1 can no longer be bound and thus bio-neutralized (see FIG ).
  • the growth factor IGF1 has a proliferation promoting role in all previously tested tissues, including PCa and BPH tissue, thus stimulating the growth of BPH and PCa.
  • the enzyme PSA is produced approximately proportional to the prostate weight and especially in carcinomatous degenerated tissue in turn proportional to the prostate carcinoma weight. So it comes with large tumors to high PSA levels, and this increase is usually detectable in the blood.
  • the invention relates to a composition of components for simultaneous or sequential administration or ingestion, the components comprising a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and a prostate-specific antigen inhibitor.
  • component denotes a monosubstance (optionally suspended, dispersed or in solution, etc.) or a substance mixture (likewise optionally in solution or suspended, dispersed, etc.) which contains one or more substances having the desired properties. have or correspond to this / correspond.
  • the term "simultaneous or sequential administration” means that the three active substances are administered either together (at the same time) preferably in one dose or sequentially (in several doses) in several doses, care being taken also in the case of sequential administration in that the active components exert their pharmacological / therapeutic / preventive activity simultaneously or substantially at the same time.
  • the oral route of administration is preferred.
  • 5 ⁇ -reductase inhibitor refers to substances (which substances may also be present in substance mixtures) which inhibit the activity of 5 ⁇ -reductase under physiological conditions in connection with other embodiments of the invention), it is understood that the activity of the enzyme is reduced by at least 50%, preferably at least 75%, more preferably at least 90%, and most preferably at least 95%. Ideally, the enzyme will increase in activity by at least 98%, e.g. at least 99% inhibited.
  • the activity of the enzyme is understood to mean the conversion of testosterone into 5 ⁇ -testosterone.
  • Suitable readout systems for measuring the reaction include measuring the starting substrate as well as the final product, including a suitable control, e.g. of a pilot batch without the addition of active enzyme.
  • finasteride commonly name for / V-tert-butyl-3-oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carboxamide.
  • Other known 5 ⁇ -reductase inhibitors contemplated as components of the composition of the invention are dutasteride and epristeride. Extracts of Cimicifuga racemosa are known as a source of further inhibitors. The skilled person is also able to isolate on the basis of his expertise further inhibitors with such activity. For example, libraries of low molecular weight substances of organic or inorganic origin, preferably in high-throughput screening, can be screened for the conversion of testosterone to 5 ⁇ -testosterone.
  • Screening assays are usually performed in the liquid phase, with at least one reaction batch being made for each compound to be tested.
  • the containers used are typically microtiter plates which have, for example, 96, 384 or 1536 reaction vessels.
  • Robots, conveyor systems and computer-aided control are further components of a high-throughput screening facility which are familiar to the person skilled in the art and are frequently used.
  • the assay may be designed as a "one-pot" reaction, which is generally preferred if practicable, but may also include washing and / or transfer steps. Detection schemes are based, for example, on radioactivity, luminescence or fluorescence, such as fluorescence resonance energy transfer (FRET) and fluorescence polarization (FP).
  • FRET fluorescence resonance energy transfer
  • FP fluorescence polarization
  • biochemical assays in which the target molecule exists alone, ie, outside the cellular context, usually allow for direct inference
  • cellular assays are characterized by their breadth, ie, the ability to interfere with a variety of cellular mechanisms as long as a desired phenotype or readout is achieved.
  • suitable animal models are used, such as the mouse (see the accompanying examples).
  • the thinning of substance libraries with hundreds of thousands of substances usually takes between days and weeks.
  • An experimental high-throughput screen can be complemented or even replaced by a virtual screen.
  • Virtual or computer-based screening approaches rely on structural information. If the structure of the target molecule is known, then methods are used which are subsumed under the term "docking.” However, if several substances binding to the target molecule are structurally known, then methods for pharmacophore modeling can be used with the aim design new, equally binding substances.
  • the readout system is an antibody specific for the 5 ⁇ -testosterone, which does not recognize testosterone. The binding of such antibodies to the 5 ⁇ -testosterone can be detected for example via a label of the antibody.
  • 5 ⁇ -reductase-2 also referred to as 5 ⁇ -reductase type 2
  • 5 ⁇ -reductase 1 also referred to as 5 ⁇ -reductase type 1
  • the 5 ⁇ -reductase inhibitor according to the invention inhibits 5 ⁇ -reductase-2 and / or 5 ⁇ -reductase-1.
  • the 5 ⁇ -reductase inhibitor according to the invention is a 5 ⁇ -reductase-2 inhibitor.
  • estrogen receptor ⁇ -agonist is also known in the art and refers to a substance (which may also be present in a substance mixture) which activates the activity of the ⁇ -subtype estrogen receptor (ER ⁇ ), this receptor being several years ago by Gustafsson's group as the second estrogen receptor (ER) (Kuiper, GGJM et al., Endocrinology 139, 4252-4263 (1998)).
  • this ER ⁇ (the old, long known ERa) was in search of ER ⁇ is expressed at high levels in the prostate and the endogenous ligand of ER ⁇ in the prostate is said to be 5 ⁇ -androstane-3 ⁇ , 17 ⁇ -diol (3 ⁇ -diol), which is a 5 ⁇ DHT metabolite
  • the 5 ⁇ -diol is thought to have a 5 ⁇ DHT antagonist effect, thus stimulating the 5 ⁇ DHT Prostate growth, including the growth of prostate cancer, while 3ßAdiol proliferation inhibiting effect.
  • Activation of ER ⁇ in the prostate or carcinoma tissue inhibits proliferation and stimulates programmed cell death (apoptosis).
  • Activation of the ER ⁇ by the component of the present invention is at least 30%, preferably at least 50%, more preferably at least 75%, and most preferably at least 100% as compared to a suitable negative control (e.g., a trial in which the component is omitted ).
  • the degree of activation is at least 200%, such as at least 500%, or at least 1000%, compared to the negative control.
  • suitable estrogen receptor ⁇ -agonists known in the art are the apigenin from the plant Vitex agnus castus and the silybinin from the plant Silybum marianum. Even in the case of this type of inhibitors, the skilled person is able to isolate other suitable substances, for example from libraries of low molecular weight substances.
  • a suitable assay for finding estrogen receptor ⁇ -agonists is a binding assay using recombinant ER ⁇ protein as the target molecule.
  • Suitable detection schemes are presented above in the context of the description of high-throughput assays for the detection of reductase inhibitors that can be used mutatis mutandis herein.
  • the activation of ER ⁇ by an estrogen receptor ⁇ -agonist of the present invention can be detected in cellular or in vivo assays.
  • cells transfected with a report gene can be used, the report gene being expressed as a function of the activation state of ER ⁇ .
  • Further suitable tests for the isolation or testing of the abovementioned inhibitors can be presented on the basis of the teaching of WO99 / 47149.
  • prostate-specific antigen inhibitor is also well known in the art and refers to substances which inhibit the enzymatic activity of PSA Inhibitors known in the art include isoflavines such as tectorigenin New prostate specific antigen inhibitors may also be derived from low molecular weight libraries
  • the inhibition of PSA secretion by adding inhibitors can be determined in vitro in the culture supernatants of suitable cells, For example, LNCaP cells are measured. LNCaP cells are PSA-producing cells derived from a human prostate carcinoma. The ATCC accession number of LNCaP cells is CRL-1740.
  • the solution according to the invention of the technical problem mentioned above breaks new ground in that a therapeutic effect based on a monosubstance is achieved via a combination of components which each attack at a different critical point in the aetiology of said prostatic diseases is far superior (see schematic diagram in Fig. 9).
  • Therapy with the composition according to the invention inhibits the 5 ⁇ -reductase, the adverse influence of the inhibition of the formation of 3 ⁇ -adiole is compensated by concomitant administration of the ER ⁇ agonist (see Fig. 2).
  • the (substantially) simultaneous therapy with a PSA inhibitor has particularly strong inhibitory effects on PSA secretion and thus inhibits the bioavailability of IGF1 and thus the proliferation-stimulating effect of this growth factor.
  • the PSA inhibitor will further inhibit the secretion of VEGF and thus inhibit neovascularization.
  • the circulus vitiosus mentioned above in connection with PSA expression is thus disrupted by inhibition of PSA secretion.
  • composition of the invention is characterized by synergistic effects.
  • the effect obtained after administration of the composition according to the invention statistically significantly exceeds the theoretical effect which results from adding the effects of the individual components (5 ⁇ -reductase inhibitor, ER ⁇ agonist, PSA inhibitor).
  • Synergistic effects are shown for a number of exemplary / preferred compositions of the invention in Figure 10 in conjunction with Example 4.
  • an extract of Cimifuga racemosa is used as the 5 ⁇ -reductase inhibitor.
  • Extracts from this plant can be made from the various components of the plant, preferably using rhizomes, leaves, roots, stems and / or petals.
  • Preferred extractants are supercritical CO 2 and mixtures of water with organic solvents.
  • the extract of Cimicifuga racemosa is an aqueous-ethanolic extract of Cimicifuga rootstock.
  • An example of how such an extract of Cimicifuga racemosa can be made is described in WO99 / 47149.
  • An example of an aqueous-ethanolic extract of Cimicifuga rootstock is the extract referred to herein as CR BNO 1055.
  • the invention relates to a composition, wherein finasteride is used as 5 ⁇ -reductase inhibitor.
  • Finasteride and its pharmacological properties are known in the art. Not known were the advantageous properties in combination with the other components of the composition according to the invention for the treatment of said prostate diseases.
  • an extract of Vitex agnus castus or of Silybum marianum is used as the source of an estrogen receptor ⁇ -agonist.
  • extracts from these plant species have been shown to exhibit the activity of an ER ⁇ agonist.
  • apigenin Jarry, H. et al., Planta Med. 69, 945-947 (2003)
  • Silybinin isolated from Silybum marianum Silybum marianum
  • Essentially all constituents of the particular plant can be used as the basis for the extracts according to the invention. These include bark, branches, seeds, fruits and logs. Rhizomes, stems, leaves and / or petals of the plants are preferably used for the preparation of the extracts. Preferred solvents used for extraction are supercritical CO 2 and mixtures of water with organic solvents.
  • compositions in which ⁇ -agonist, silybinin or apigenin, is used as the estrogen receptor can be isolated for use in the composition of the invention from the extracts of the aforementioned plants.
  • these substances whose structure is known can be prepared by the means of organic chemical synthesis.
  • an extract of Belamcanda chinensis is used as the inhibitor or as the source of an inhibitor of the prostate-specific antigen for the composition.
  • Essentially all constituents of the plant can be used as the basis for the extract. These include bark, branches, seeds, fruits and logs. Rhizomes, stems, leaves and / or petals of the plants are preferably used for the preparation of the extracts.
  • Preferred solvents used for extraction are supercritical CO 2 and mixtures of water with organic solvents.
  • the invention relates to a composition characterized by the use of tectorigenin as a prostate-specific antigen inhibitor.
  • tectorigenin can be isolated from the extracts of Belamcanda chinensis. The substance is shown in its structural formula in WO 99/47149. Like the extract of Belamcanda chinensis, it has PSA-inhibitory activity and can thus be considered as or one of the active principles in the extracts of Belamcanda chinensis.
  • essentially all components of the plant can be used as starting material for the exacre. These include bark, branches, seeds, Fruits and logs. Rhizomes, stems, leaves and / or petals of the plants are preferably used for the preparation of the extracts.
  • Preferred solvents used for extraction are supercritical CO2 and mixtures of water with organic solvents.
  • a pure substance which also occurs as an effective part of the extract
  • sylbinine is a pure substance that also occurs as part of the extract of Silybum marianum.
  • apigenin and Vitex agnus castus extract as well as between tectorigenin and Belamcanda chinensis extract, which each have the same profile of action.
  • a composition is the subject of the invention, which contains - as active agents - three pure substances, for example, the combination No. 10 shown above.
  • the composition is a drug.
  • pure substances or substantially purified extracts and not only standard formulated extracts be used, although the latter possibility is not excluded according to the invention.
  • extract formulated by default is familiar to the person skilled in the art and relates to the formulation instructions as can be found in the international pharmacopoeias, for example the German or European Pharmacopoeia (DAB or EUPHARM).
  • the medicaments preferably contain a pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients include pharmaceutically acceptable carriers or excipients and pharmaceutically acceptable diluents. Examples of suitable carriers are known in the art and monographed in international pharmacopoeias as pharmaceutical excipients.
  • the drugs may be administered to an individual at a suitable dosage.
  • Administration is preferably oral, parenteral or subcutaneous. Particularly preferred is oral administration.
  • the amount of dosage will be determined by the attending physician and will depend essentially on the clinical factors. These factors are well known in medicine and science and include, for example, body size or weight, body surface area, age, sex, and general health of the patient. the specific composition to be administered, the duration of treatment, the route of administration and the possible simultaneous treatment with other medicinal products.
  • a typical dose may be, for example, in a range between 0.001 and 5000 mg of the extractives or the pure substances, with doses below or above this exemplary range, especially taking into account the factors mentioned above, are conceivable.
  • the dose should be in the range of between 1 mg and 1000 mg units per day.
  • the dose should be in the range of 1 ⁇ g to 10 mg units per kilogram of body weight per minute.
  • finasteride it is preferred to apply a dose of about 1 mg to about 10 mg finasteride per day, more preferably 5 mg per day.
  • an extract of Cimicifuga racemosa it is preferred to apply a dose of from about 10 mg to about 100 mg per day, more preferably from about 40 mg to about 60 mg per day.
  • Preferred doses in the mouse or in the mouse model shown in the examples are in the range between 2 and 3 mg per day.
  • composition according to the invention which is a dietary supplement or a functional food having a preventive and / or therapeutic effect.
  • extracts are preferably used.
  • the various components are preferably formulated together in one dose.
  • the ingestion and preferably the regular use of the dietary supplement according to the invention is for the prevention of prostate diseases, such as benign prostate hyperplasia and, in particular, prostate carcinoma.
  • the invention further relates to the use of a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and an inhibitor of the prostate-specific Antigen for the manufacture of a medicament for the prevention or treatment of prostate disease.
  • the invention relates to the use of a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist and an inhibitor of the prostate-specific antigen for the preparation of a dietary supplement for the prevention of a prostate disease.
  • prostate disease is a prostate carcinoma or a benign prostatic hyperplasia.
  • the invention provides a method of treating a patient having a prostate disease, comprising administering a combination of a 5 ⁇ -reductase inhibitor, an estrogen receptor ⁇ -agonist, and a prostate-specific antigen inhibitor, simultaneously or sequentially.
  • FIG. 1 is a diagrammatic representation of FIG. 1:
  • FIGS. 1a and b make it reasonable to combine a 5 ⁇ -reductase inhibitor with an ER ⁇ agonist (FIG. 2). These new therapeutic approaches will be discussed further.
  • FIG. 2 is a diagrammatic representation of FIG. 1
  • FIG. 3 is a diagrammatic representation of FIG. 3
  • Fig. 3a shows the deleterious effects of increased PSA secretion of the prostate by inactivating the IGF1 binding protein is released intraprostatisch increased IGF1, which leads to the stimulation of prostate cancer tissue. This leads to a vicious circle, which can be broken by inhibition of PSA secretion (Figure 3b).
  • FIG. 4 is a diagrammatic representation of FIG. 4
  • the growth of the prostate of prepubertal rats can be greatly stimulated by administration of testosterone.
  • This stimulation is achieved by administration of the synthetic 5 ⁇ -reductase inhibitor finasteride, as well as by Cimicifuga racemosa Extract (CR) significantly inhibited (Fig. 4a).
  • Measurement of 5 ⁇ -DHT, the product of 5 ⁇ -reductase shows in both treatments a marked reduction of this hormone compared to the control-treated animals, which is evidence for the inhibition of 5 ⁇ -reductase by Cimicifuga racemosa extract (FIG. 4b).
  • FIG. 5 is a diagrammatic representation of FIG. 5
  • LNCaP cells The growth of LNCaP cells is dose-dependently inhibited in very low concentrations by Cimicifuga racemosa extract.
  • FIG. 6 is a diagrammatic representation of FIG. 6
  • FIG. 6b The tumor volumes at the end of the experiment of all animals are shown in Fig. 6b.
  • Figures 6b and 6c show the lower tumor volumes and the significantly lower serum PSA levels at the end of the trial of the CR-treated animals compared to the controls.
  • FIG. 7 is a diagrammatic representation of FIG. 7
  • Tectorigenin isolated from Belamcanda chinensis inhibits PSA secretion of LNCaP cells under in vitro conditions. This property of tectorigenin is also found in the extract of Belamcanda chinensis (BC).
  • FIG. 8 is a diagrammatic representation of FIG. 8
  • Figure 8a shows a marked inhibition of the rate of LNCaP-induced tumors in male nu / nu mice. 3 out of 18 BC treated animals developed tumors. The mean values of the end volumes of the tumors of the BC- treated animals were only marginally smaller than controls ( Figure 8b) as an extremely large tumor developed in 1 animal.
  • FIG. 9 is a diagrammatic representation of FIG. 9
  • FIG. 9 shows an attempt to graphically illustrate the interactions of the components of the composition according to the invention.
  • Combination therapy with Cimicifuga racemosa extract will inhibit 5 ⁇ -reductase, the adverse effect of inhibiting the formation of 3 ⁇ -adiole may be compensated for by concomitant administration of the ER ⁇ agonist in Silybum marianum (or Agnus castus).
  • An additional therapy with a Belamcanda chinensis extract has particularly strong inhibitory effects on PSA secretion and will thus inhibit the bioavailability of IGF1 and thus the proliferation-stimulating effect of this growth factor.
  • Both the Silybum marianum and the Belamcanda chinensis extract would cause the secretion of VEGF and thus the inhibition of neovascularization.
  • FIG. 10 is a diagrammatic representation of FIG. 10
  • Example 1 Inhibitory effect of Cimicifuga racemosa extracts on a human prostate cell line
  • the Cimicifuga racemosa (CR) extract contains strong 5 ⁇ -reductase inhibiting principles.
  • Cimicifuga racemosa extract inhibits the proliferation of LNCaP cells.
  • Example 2 Inhibitory effect of Cimicifuga racemosa extracts in vivo
  • nu / nu mice were inoculated subcutaneously with LNCaP cells (1 million per animal) and tumor growth was administered with Cimicifuga racemosa extract in two doses with the feed.
  • the aqueous-ethanolic extract of Cimicifuga rootstock with the internal name CR BNO1055 was used.
  • Figure 6 clearly demonstrates inhibition of the incidence of tumors as well as slower growth of the few developing tumors compared to the non-CR treated control animals.
  • Example 3 Effect of Beiamcanda chinensis extracts or tectorigenin in vitro and in vivo
  • silylbinin (Seidlova-Wuttke et al., Loc. Cit.) Also has an ER ⁇ -agonistic effect. This has led to the investigation of the effect of silybinin on LNCaP cell growth, PSA secretion, etc., demonstrating that silybinin is a pure ER ⁇ agonist that inhibits the growth of LNCaP cells, PSA secretion, and the Production of the vascular endothelial growth factor (VEGF) inhibits. Increased production of VEGF is the result of rapid tumor growth, which makes capillary regeneration indispensable for progressive tumor growth, thus enabling the rapid growth of tumors. Its inhibition has led to the development of VEGF antagonists, which are currently undergoing clinical testing to inhibit tumor growth.
  • VEGF vascular endothelial growth factor
  • Tectorigenin isolated from Beiamcanda chinensis inhibits PSA secretion of LNCaP cells under in vitro conditions. These properties of tectorigenin are also found in the total extract ( Figure 7). In addition, the gene expression of a coactivator of the androgen receptor is inhibited, so that possibly existing androgens can act more weakly by the androgen receptor.
  • Incubation medium prepared the appropriate working solutions.
  • the testosterone - stock solution was prepared at a concentration of 10 "2 M in DMSO and diluted with incubation medium also.
  • the MTT proliferation test is a quantitative assay for detection of living cells.
  • the vitality indicator is mitochondrial metabolic activity.
  • MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) is converted by the mitochondria of vital cells in an NADH-dependent reaction to formazans.
  • the formed formazans are colored and colorimetrically detectable. There is direct proportionality between color intensity and vitality of the cells.
  • the LNCaP cells were incubated in 75 cm 2 bottles in a Cytoperm 2 incubator (Heraeus, Hanau) at 37 ° C, 10% CO 2 and 90% relative humidity and scored microscopically daily to exclude contamination. Every third day a change of medium was made; once a week, the cells were subcultured. For this purpose, the medium was filtered off with suction and, after a washing step with PBS, replaced by 6 ml of trypsin solution. The bottles were incubated for a maximum of 5 minutes at 37 ° C. until the cells dissolved from the bottom of the bottle. Subsequently, the cell suspension in 10 ml of permanent culture medium (PKM) was added and the bottle rinsed once with medium. The cells were sedimented (300 g, 10 minutes) and washed once with PKM. Finally, the cells were counted with a Neubauer counting chamber (Brand, Wertheim).
  • PPM permanent culture medium
  • the cell suspension was adjusted to 80,000 cells / ml and 250 ul of this suspension per well (Well) of a 96-WeII plate plated. The cells were incubated for an additional 24 hours at 37 ° C.
  • the incubation medium contained testosterone at a concentration of 10 nM.
  • the extracts or tectorigenin and DMSO were added in a volume of 30 ⁇ l each.
  • the concentrations of these solutions were either 500 ⁇ g / ml (SM, CR, VAC, tectorigenin) or 1000 ⁇ g / ml (BC).
  • the final concentrations in the cell culture were 51.7 ⁇ g / ml (SM, CR, VAC, tectorigenin) and 103.4 ⁇ g / ml (BC). In the graph, these concentrations are referred to as 50 and 100 ⁇ g / ml, respectively.
  • the pipetting scheme was:
  • Basal secretion • 200 ⁇ l medium
  • Confidence intervals were calculated to show statistically significant differences between the combination approaches and the cumulative effects of the individual components. Overlapping confidence intervals do not indicate a statistically significant difference between the approaches compared. For non-overlapping confidence intervals, on the other hand, a statistically significant difference can be assumed. Fundamentals of the calculation of the confidence intervals of the mean MTT values for the measured combination approaches and the MTT values calculated from the individual components of the combination approaches:
  • a treatment effect is indicated by the difference in MTT values between treatment and control.
  • the difference between treatment and control was calculated by the difference in means; the corresponding variance was formed from the sum of the variances of the two treatments.
  • the sum of the MTT values of the individual extracts contained in the combination was calculated; the corresponding variances were calculated from the sum of the variances of the MTT values of the respective individual extracts.

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Abstract

L'invention concerne une composition à base de composants à administration ou prise simultanée ou séquentielle, ces composants comprenant un inhibiteur de la 5α-réductase, un β-agoniste des récepteurs des oestrogènes et un inhibiteur de l'antigène spécifique de la prostate. L'invention concerne également l'utilisation d'un inhibiteur de la 5α-réductase, d'un β-agoniste des récepteurs des oestrogènes et d'un inhibiteur de l'antigène spécifique de la prostate pour produire un médicament destiné à prévenir ou traiter une maladie de la prostate. L'invention concerne en outre l'utilisation d'un inhibiteur de la 5α-réductase, d'un β-agoniste des récepteurs des oestrogènes et d'un inhibiteur de l'antigène spécifique de la prostate pour produire un complément alimentaire pour prévenir une maladie de la prostate. Dans des modes de réalisation préférés de cette composition ou de cette utilisation, l'inhibiteur de la 5α-réductase utilisé est un extrait de Cimifuga racemosa, le β-agoniste des récepteurs des oestrogènes est un extrait de Vitex agnus castus ou de Silybum marianum et l'inhibiteur de l'antigène spécifique de la prostate est un extrait de Belamcanda chinensis.
EP06762663A 2005-07-19 2006-07-17 Preparation combinee, en particulier pour traiter le cancer de la prostate Withdrawn EP1904018A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06762663A EP1904018A2 (fr) 2005-07-19 2006-07-17 Preparation combinee, en particulier pour traiter le cancer de la prostate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05015692A EP1745796A1 (fr) 2005-07-19 2005-07-19 Preparation combinée pour le traitment du cancer de la prostate
PCT/EP2006/007027 WO2007009734A2 (fr) 2005-07-19 2006-07-17 Preparation combinee, en particulier pour traiter le cancer de la prostate
EP06762663A EP1904018A2 (fr) 2005-07-19 2006-07-17 Preparation combinee, en particulier pour traiter le cancer de la prostate

Publications (1)

Publication Number Publication Date
EP1904018A2 true EP1904018A2 (fr) 2008-04-02

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EP05015692A Withdrawn EP1745796A1 (fr) 2005-07-19 2005-07-19 Preparation combinée pour le traitment du cancer de la prostate
EP06762663A Withdrawn EP1904018A2 (fr) 2005-07-19 2006-07-17 Preparation combinee, en particulier pour traiter le cancer de la prostate

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP05015692A Withdrawn EP1745796A1 (fr) 2005-07-19 2005-07-19 Preparation combinée pour le traitment du cancer de la prostate

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EP (2) EP1745796A1 (fr)
WO (1) WO2007009734A2 (fr)

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Publication number Priority date Publication date Assignee Title
JP5626164B2 (ja) 2011-07-26 2014-11-19 日本精工株式会社 ステアリングコラム用支持装置

Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
DE19812204A1 (de) 1998-03-19 1999-11-04 Plantamed Arzneimittel Gmbh Verwendung von Extrakten aus Cimicifuga racemosa und Belamcanda sinensis als estrogenartiges organselektives Arzneimittel ohne uterotrope Wirkung
DE10123503A1 (de) 2001-05-15 2002-11-21 Bionorica Ag Verwendung von Extrakten und Zubereitungen aus Irisgewächsen und Tectorigenin als organselektives Arzneimittel zur Behandlung von sexualhormon-abhängigen Erkrankungen des Urogenitaltraktes
DE10127897B4 (de) * 2001-06-08 2006-04-20 Bionorica Ag Manteltablette mit Pflanzentrockenextrakten
DE10146159A1 (de) 2001-09-19 2003-04-10 Bionorica Ag Verwendung von Extrakten aus Cimicifuga-Arten als organselektives Arzneimittel zur Behandlung von sexualhormonabhängigen Erkrankungen des Urogenitaltraktes
FR2842421B1 (fr) * 2002-07-16 2004-10-15 Besins Int Belgique Nouvelles compositions pharmaceutiques a base d'inhibiteurs de la 5-alpha-reductase et leurs utilisations

Non-Patent Citations (1)

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Title
See references of WO2007009734A2 *

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WO2007009734A3 (fr) 2007-04-19
EP1745796A1 (fr) 2007-01-24

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