Medication for treating endometriosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of dopamine agonist (for instance, amantadine, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, ropinirole and pramipexole) for production of medication for treatment and prevention of endometriosis.

EFFECT: reduction of number of active endo-metrioid niduses, in treated niduses signs of atrophic or degenerative tissues were observed, ie reduction of number of endometrial glands under action of cabergoline.

14 cl, 6 dwg, 2 tbl, 2 ex

The present invention relates to medicines for the treatment of endometriosis.

Endometriosis is a benign chronic gynecological disease. It can be defined as the presence of endometrial tissue containing both glandular epithelium and stroma outside the uterine cavity. It is a benign gynecological disorder, in which subpopulations of female patients may develop aggressive disease. Endometriosis is associated with a variety of painful symptoms, including dysmenorrhea, dyspareunia, pelvic pain and reduced fertility.

It is known that for the development of endometriosis can be an important angiogenesis (the process by which from pre-existing vessels, the formation of new blood vessels) and that in the formation of blood vessels plays the role of vascular permeability factor/endothelial growth factor vascular (VP/VEGF), both in physiological and pathological angiogenesis. The potential efficacy of antiangiogenic therapy for the treatment of endometriosis was evaluated with the use of research using human endometrial tissue transplanted into Nude mice with weakened immune systems. Four different antiangiogenic agent was administered three weeks after transplantation of endometrial the x explants (Nap et al, 2004). All four inhibitors were able to reduce the size of rooted explants, and the formation of new blood vessels stopped. However, the known antiangiogenic agents are highly toxic, and it is difficult to implement in clinical practice in humans.

Now it was unexpectedly found that compositions containing a dopamine agonist, can be used to treat endometriosis.

Thus, according to the present invention proposed the use of a dopamine agonist in the manufacture of medicinal products for the treatment and/or prevention of endometriosis. According to the present invention has also proposed the use of a dopamine agonist in the treatment and/or prevention of endometriosis. Here, the term "endometriosis treatment" includes treatment to reduce (or remove) endometrial tissue is present outside the uterine cavity (e.g., reduction or removal of endometriotic foci), and/or treatment to reduce and/or alleviate one or more symptoms associated with endometriosis (for example, treatment for alleviating and/or reducing symptoms of dysmenorrhea; treatment for alleviating and/or reducing symptoms of dyspareunia and/or treatment to alleviate and/or reduce pelvic pain). The term "endometriosis treatment" includes treatment to reduce the number of elements of u, or the reduction of the sizes of the elements of the endometrial tissue, present outside the uterine cavity (for example, reducing the number and/or size of the endometriotic foci). The term "endometriosis treatment" includes treatment to reduce the number of endometrial glands. The term "endometriosis treatment" includes treatment, leading to one or more of: a significant reduction in the percentage of active endometriotic lesions; significant loss of cellularity and organizations in endometriotic foci, which represents a characteristic of atrophic or degenerative tissue; and a significant reduction in the number of new blood vessels in endometriotic foci. The term "endometriosis treatment" includes treatment to reduce the number and/or size of endometriotic lesions in one or more than one of ovary, fallopian-pryamokishechnye deepening, Sacro-uterine ligaments, the posterior surfaces of the uterus, the broad ligament, the rest of the pelvic peritoneum, intestines, urinary tract (including, for example, bladder and/or ureter).

The term endometriosis includes, for example, peritoneal endometriosis, ovarian endometriosis and deep endometriosis.

Here the term dopamine agonist means a compound that acts like dopamine, for example a drug that interact with receptors dopamine (i.e. specific binding) to mimic the action of dopamine. It is not VK is uchet connection which is the only "dopaminergic substances", that is, only compounds that, through various mechanisms of action, increase the levels of dopamine. The term dopamine agonist does not include the bridge interoperability disclosed in US 6359130.

It was previously shown that dopamine agonists useful in the treatment or prevention of ovarian hyperstimulation syndrome (OHSS) (WO 2006117608). It is a condition in which significantly increases vascular permeability of capillaries. It was found that dopamine agonists can reverse this effect. However, the condition of endometriosis and the potential efficacy of antiangiogenic therapy for the treatment of endometriosis, there is not disclosed.

In the context of this invention, the dopamine agonists include, without limitation, amantadine, parlodel, cabergoline, chinagrid, lisuride, pergolid, ropinirole and pramipexol. The preferred dopamine agonist for use in the present invention is cabergoline. The preferred dopamine agonist for use in the present invention is chinagrid. The so-called "partial dopamine agonists (e.g., terguride) can also be used in accordance with the invention. However, preferably the use of dopamine agonists.

Prepact the positive use one dopamine agonist.

Dopamine agonist can be entered in the dose (for example, an oral dose of the patient-a man from 25 micrograms per day to 80 mg/day, preferably from 50 micrograms per day to 5 mg/day, more preferably from 300 micrograms per day to 1 mg/day; the appropriate dose within this range is dependent on the use of a dopamine agonist and obvious to a person skilled in this technical field.

In the preferred embodiment, the dopamine agonist is a cabergoline. Preferably cabergoline injected dose (e.g., oral dose to the patient is a person) from 0.01 to 12.5 mg/week, preferably 0.1 to 10 mg/week, more preferably 0.5 to 5 mg/week, more preferably at a dose of 3.5 mg/week of 4 mg/week. Dopamine agonist can be entered in the form, for example, a single daily dose (eg, 0.1 mg/day to 5 mg/day, 0.2 mg/day 1 mg/day, such as 0.5 mg/day); or the daily dose can be divided into two or more curiosi for receiving at different times during a 24-hour period. Dopamine agonist (cabergoline) may be introduced in the form of a daily dose of the levels listed above, or equivalent doses, for example, once a week, twice a week or every two days. In one scheme, a dopamine agonist (e.g., cabergoline) is administered in a total dose of 3.5 to 12.5 mg per week (for example, 4 mg per week, 7 mg per week, 10 mg/week).

In another GP is owenii a dopamine agonist is chinagrid. Preferably chinagrid injected dose (for example, an oral dose of the patient-person) at 25 ÷ 1000 micrograms/day, preferably 25-500 micrograms/day, more preferably 25-300 mcg/day. Dopamine agonist can be entered in the form, for example, a single daily dose or daily dose can be divided into two or more curiosi for receiving at different times during a 24-hour period. Dopamine agonist (chinagrid) can be introduced in the form of a daily dose of the levels listed above, or equivalent doses, for example, once a week, twice a week or every two days.

In another embodiment, the dopamine agonist is a parlodel. Preferably parlodel injected dose (e.g., oral dose to the patient is a man) 10-80 mcg/day, preferably 10-40 mg/day.

In one embodiment, the dopamine agonist is used as the only medical treatment of endometriosis. In other words, a dopamine agonist may be used in the absence of other medical or surgical treatments (e.g., in the absence of danazol).

In another embodiment the administration of a dopamine agonist may be combined with other medical or surgical treatment of endometriosis (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and/or on monaldini drugs (danazol, oral contraceptives (OC), medroxyprogesterone acetate, other progestins, agonists and antagonists of gonadotropin-releasing hormone (GnRH), aromatase inhibitors)). In another embodiment of the surgical treatment or medication can be used before, during or after treatment with a dopamine agonist. These embodiments are discussed in more detail in the examples below.

It was also found that the introduction of a dopamine agonist to a patient in need this, can provide significant clinical advantages, such as, for example, a significant decrease in the percentage of active endometriotic lesions; significant loss of cellularity and organizations in endometriotic foci, which represents a characteristic of atrophic or degenerative tissue; and a significant decrease in the number of new blood vessels in endometriotic foci.

Medicines on the basis of dopamine agonists also have the advantage of tolerance to high doses, as well as the safety and well-documented reports on the clinical use.

It was also found that a dopamine agonist (e.g., cabergoline), you can enter in for long periods of time (e.g., 1-3 weeks (for example, 1-21 days, for example 1-14 days), from 1 day to 3 months, from 1 day to six months, from 1 day is about 12 months, from 1 day to 2 years or longer) with a therapeutically useful effect and low risk of side effects. The introduction may be continuous, for example in the form of daily or weekly dose, or may be interrupted by one or more intervals with a duration of, for example, multiple (e.g. 1-3) weeks or more (e.g. 1-3) months. Dopamine agonist can be entered while the pain remains (or other symptom).

A dopamine agonist (e.g., cabergoline, chinagrid) you can enter a pregnant subject.

Treatment or prevention of endometriosis can be associated with a decrease in the number of endometrial glands.

In the example of the invention on the growth factor vascular endothelial (VEGF) as a factor in the development of endometriosis can be provided with directional effects of the dopamine agonist. Apparently, in the process of angiogenesis is involved mainly isoforms VEGF121 and VEGF165 (Watkins, R.H., et al., Am. J. Physiol. 1999, vol. 276, pp.858-67). It was identified two specific endothelial cell membrane receptor of VEGF, VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (Flk-1/KDR). Apparently, in the regulation of angiogenesis and the formation and development of blood vessels involved mainly VEGFR-2.

On VEGFR-2 (KDR) as a factor in the development of endometriosis can, thus, be rendered directional effects of the dopamine agonist. On Notch-4 as a factor in the development of endometriosis may shall be provided directional effects of the dopamine agonist. For VEGF, VEGFR-2 and Notch-4 as factors in the development of endometriosis can be provided with directional effects of the dopamine agonist. Other mechanisms of action of dopamine agonist included in the scope of the invention.

A dopamine agonist is administered in the form of a pharmaceutically acceptable preparation. The drugs can be introduced in accordance with the invention in pharmaceutically acceptable compositions, which may possibly contain pharmaceutically acceptable salt, buffering agents, preservatives and excipients. Pharmaceutical preparations containing the agonist(s) of dopamine as the active agents are well known in the art and are commercially available. For example, cabergoline is available under the registered trademarks Cabaser and Sogilen/Dostinex. The use of such commercially available drugs dopamine agonists in the treatment of endometriosis is included in the scope of the invention.

The choice of the method of administration depends on the severity and the severity of the condition to be treated, and the required dose. Any route of administration providing the desired therapeutic effect without unacceptable adverse effects, appropriate for practical implementation of the invention. Such methods of administration may include oral, rectal, local, transdermal, sublingual, intramuscular, parenteral, intravenous, intracavitary, vaginal method and BB is Denia using adhesive matrix for use during the surgical intervention. Various methods of making compositions for use in accordance with the invention are described in Handbook of Pharmaceutical Excipients, Third Edition, American Pharmaceutical Association, USA and Pharmaceutical Press, UK (2000), Pharmaceutics - The Science of Dosage Form Design, Churchill Livingston (1988).

In the preferred embodiment introduction is oral. Compositions suitable for oral administration include capsules, starch wafers, tablets, syrups, elixirs or cakes.

According to the present invention, in another aspect, a method of treatment or prevention of endometriosis, including the stage of introduction to a patient in need, a dopamine agonist.

Preferably, the dopamine agonist is administered in the form of pharmaceutical preparation containing one or more than one dopamine agonist as an active ingredient.

Dopamine agonist can be entered in the dose (for example, an oral dose of the patient-a man from 25 micrograms per day to 80 mg/day, preferably from 50 micrograms per day to 5 mg/day, more preferably from 300 micrograms per day to 1 mg/day; the appropriate dose within this range is dependent on the use of a dopamine agonist and obvious to a person skilled in this technical field.

In the preferred embodiment, the dopamine agonist is a cabergoline. Preferably cabergoline injected dose (e.g., orally, the dose to the patient is a person) from 0.01 to 12.5 mg/week, preferably 0.1 to 10 mg/week, more preferably 0.5 mg to 5 mg/week, more preferably at a dose of 3.5 mg/week of 4 mg/week. Dopamine agonist can be entered in the form, for example, a single daily dose (eg, 0.1 mg/day to 5 mg/day, 0.2 mg/day 1 mg/day, for example, 0.5 mg/day); or the daily dose can be divided into two or more curiosi for receiving at different times during a 24-hour period. Dopamine agonist (cabergoline) may be introduced in the form of a daily dose of the levels listed above, or equivalent doses, for example, once a week, twice a week or every two days. In one scheme, a dopamine agonist (e.g., cabergoline) is administered in a total dose of 3.5 to 12.5 mg per week (for example, 4 mg per week, 7 mg per week, 10 mg/week).

In another embodiment, the dopamine agonist is chinagrid. Preferably chinagrid injected dose (for example, an oral dose of the patient-person) at 25 ÷ 1000 micrograms/day, preferably 25-500 micrograms/day, more preferably 25-300 mcg/day. Dopamine agonist can be entered in the form, for example, a single daily dose or daily dose can be divided into two or more curiosi for receiving at different times during a 24-hour period. Dopamine agonist (chinagrid) can be introduced in the form of a daily dose levels specified above, or as equivalent to the doses, for example, once a week, twice a week or every two days.

In another embodiment, the dopamine agonist is a parlodel. Preferably parlodel injected dose (e.g., oral dose to the patient is a man) 10-80 mg/day, preferably 10-40 mg/day.

The introduction of a dopamine agonist may be combined with other medical or surgical treatment of endometriosis (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) and/or hormonal drugs (danazol, oral contraceptives (OC), medroxyprogesterone acetate, other progestins, agonists and antagonists of gonadotropin-releasing hormone (GnRH), aromatase inhibitors)). In another embodiment of the surgical treatment or medication can be used before, during or after treatment with a dopamine agonist.

The authors of this application have found that a dopamine agonist (e.g., cabergoline), you can enter in for long periods of time (e.g., 1-3 weeks (for example, 1-21 days, for example 1-14 days), from 1 day to 3 months, from 1 day to six months, from 1 day to 12 months from 1 day to 2 years or longer) with a therapeutically useful effect and low risk of side effects. The introduction may be continuous, for example, in the form of daily or weekly dose of the Il which may be interrupted by one or more interruptions duration, for example, multiple (e.g., 1-3) weeks or more (e.g., 1-3) months. Dopamine agonist can be entered while the pain remains (or other symptom).

The patient may be pregnant.

Treatment or prevention of endometriosis can be associated with a decrease in the number of endometrial glands.

The present invention will now be illustrated with reference to examples and the accompanying graphics.

DESCRIPTION of GRAPHIC MATERIALS

Figure 1 shows the percentage of active lesions according to a study on animals, discussed below, for the control group and groups treated with low dose (0.05 mg/kg/day) and high dose (0.1 mg/kg/day) of cabergoline; Figa shows the relationship gland/stroma in three established groups (under the low and high dose of cabergoline ("Cb2") stroma was more and glands was lower than in control animals (*p<0,05)).

Figure 2 shows the blood vessels (mm³for the control group and groups of low and high doses.

Figure 3 shows the percentage of "Mature" and "newly" blood vessels in animals from the control group and groups of low and high doses.

Figure 4 shows the proliferation index for the control group and groups of low and high doses.

Figure 5 shows the relative expression of VEGF, VEGFR-2 (KDR), Notch-4, Ang-1 and Wnt-1 the La control groups and groups of low and high doses.

On Figa shows the presence of the dopamine receptor type 2 (Dp-r2 and VEGF in endometrial implants animals in the three established groups (control group and the groups of low and high doses).

On Figb shows the relative expression of VEGF, VEGFR-2 (KDR) and D2R in endometriotic foci (left column) and the endometrium (right column).

Example 1

Experimental animal model of endometriosis was developed in Nude mice by injecting fragments of human endometrium. Female mice (Hsd: Athimic Nude-nu, Harlan Iberica S.L, Barcelona, Spain) separately contained in autoclavable cells on the litter, in laminar flow filters. In area for animals maintained a temperature of 26°C With a cycle of 12 hours light, 12 hours darkness and mice were fed ad libitum autoclaved food for laboratory rodents and acidified water. All manipulations were carried out in laminar flow filters. A mixture of ketamine and medetomidine (75 µg/g ketamine and 1 mg/g of medetomidine) (Ketolar®, Parke-Davis, Espana; Domtor®, Pfizer, Spain), injected intraperitoneally (I.P. Pavlova.), used to anestesiologia mice before invasive procedures and atipamezol (Antisedan®, SmithKline Beecham, Spain), injected I.P. Pavlova. at a dose of 1 µg/g for reversing the effects of anesthesia used after invasive procedures using sterile equipment.

At the age of 5 weeks, sterile the haunted capsules release within 60 days (60-d), containing 18 mg of 17β-estradiol (Innovative Research of America, Sarasota, FL)were placed subcutaneously in the neck of each animal. In accordance with the information of the manufacturer capsules provide long-releasing hormone in serum concentrations of 150-250 pmol/l in the range of physiological levels in mice during the estrous cycle. This stable physiological levels of estrogen stimulates the growth of transplanted human endometrium and reduces the differences among different mice, due to different stages of the estrous cycle.

Four days after injection of estrogen pills made access into the abdominal cavity in the midline in the lower abdomen for the introduction of fresh human endometrium from donors after egg collection. These fragments were fixed with glue (Vetabond®, 3M Animal Care products, USA) to the peritoneum. This Protocol enables you to simulate a pathological situation retrograde menstruation occurring in women with endometriosis.

Three weeks after implantation, animals were divided into three groups. The first was a control group; the second was a group of low-dose treated with cabergoline oral dose of 0.05 mg/kg/day; and the high-dose group treated with cabergoline oral dose of 0.1 mg/kg/day. Two weeks after treatment the animals were killed, sconces and samples of endometriotic foci and analyze them, as set forth below. The results are shown in figures 1, 1A and 2-6b.

Antiangiogenic effects of dopamine agonists was assessed by immunofluorescence assay, confocal microscopy was used antibodies produced against factor von Willebrand's disease (vWF monoclonal IgG1, DAKO Corp., Denmark)present in endothelial cells and smooth muscle cells of blood vessels (monoclonal IgG2 α-SMA-FITC conjugated, de Sigma, St Louis, USA). Blood vessels that are not newly formed, surrounded by a smooth muscle layer, giving them a maturity. Identification of endothelial cells was performed using vWF, whereas Mature vessels were identified by positive staining for α-SMA. Thus, vWF+/αSMA - blood vessels were seen as new or immature, while vWF+/αSMA+ vessels classified as old or Mature blood vessels.

Morphometric study was performed to measure the area and cell density of the implants. Immunocytokine using antibody Ki-67 (monoclonal IgG1 DAKO Corp., Denmark) was performed to assess the proliferative activity of implants. Histopathological and cellular ultrastructural changes were identified using an optical microscope (OM), transmission electron microscope (FACT) and histochemical staining. Optical mikros the opium (Ω), transmission electron microscopy (FACT) and morphometry was performed to detect the presence of endometrial glands and stroma and research sub-cellular ultrastructural changes, the area of implants and cell density.

TaqMan Real-time PCR (polymerase chain reaction real-time TaqMan) and 2^-ΔΔCtused for analysis of gene expression profiles of three different markers that stimulate angiogenesis (VEGF, VEGFR-2, Notch-4), angiopoietin-1 (Ang-1), token antiangiogenesis, stimulating an increase of existing vessels and the resistance of the filter, and Wnt-1. The presence of expression of VEGF and receptor dopamine type 2 (Dp-r2) in the experimental implants, human peritoneal endometriotic lesions and endometrial demonstrated with the use of TaqMan Real-time PCR and method 2^-ΔΔCt(Figa, 6b). Similarly, this method was used to demonstrate the presence of expression of VEGFR-2 in human peritoneal endometriotic lesions and endometrial (Figb).

Statistical analysis was performed using GraphPad Instat 3.0 (GraphPad Software, San Diego, CA, USA). The study was designed to elucidate the differences in the various analyzed markers in the treatment group and the control group. Categorical data were expressed as number and percentage and numeric data were expressed as mean ± standard error of the mean (SEM), Engl is not specified. Significance was defined as p<0,05. For statistical analysis used one-way analysis of variance.

Toxicity

None of the analyzed mice died after the introduction of cabergoline. Apparently, cabergoline had no effect on the overall health of the mice, because of significant differences in body weight of mice in different treatment groups was observed (results not shown).

Results

Figure 1 shows the percentage of active lesions according to a study on animals, discussed above, for the control group and groups treated with low dose (0.05 mg/kg/day) and high dose (0.1 mg/kg/day) of cabergoline. In animals treated with low (58,6±9,7%) and high (60,4±8.4%) of the dose was a significant decrease (p=0,0169) active lesions compared with controls (89,6±5,7%). In animals treated with cabergoline (as in the group with low dose, and high dose)had significantly fewer active lesions compared with the control group. In other words, the treatment cabergoline apparently reduced the number of active endometriotic lesions in this model. OM - and-research has shown that in the control group endometriotic lesions had vysokokratnoy stroma and histological aspect of a complete reorganization and structure, which can be seen in a typical human endometrioid the loci for the E. However, in treated lesions (high and low dose of cabergoline) see loose stroma with loss of cellularity and organization; it is a characteristic atrophic or degenerative tissue. Human endometrial stroma surrounding the glandular region, was easily distinguishable from the muscle-mouse connective tissue.

These histological findings were confirmed by morphometric analysis (Figa). Although cell density statistical differences between groups were not, between groups was significant (p=0,0093) difference in relation gland/stroma, as you can see in Figa; both low and high doses of cabergoline had more of stroma and glands less than controls (*p<0,05). This indicates that treatment with cabergoline can be associated with a decrease or reduction in the number of endometrial glands.

Figure 2 shows the blood vessels (mm³for the control group and groups of low and high doses, with a distinction between "Mature" blood vessels and "newly" blood vessels. In the control group was more the share of newly-formed blood vessels (which indicates a significant angiogenesis), while in the groups of low and high doses significantly greater proportion of Mature blood vessels, indicating significantly reduced and Diogenes. It was also demonstrated histologically (results not shown). These results indicate that cabergoline significantly reduced the formation of new blood vessels (angiogenesis) in this model.

Figure 3 shows the percentage of blood vessels in the control group and the groups of low and high doses. In the control group, approximately 74% of all blood vessels are newly formed blood vessels, indicating a significant angiogenesis. On the other hand, in the groups of low and high doses of approximately 85-89% of all blood vessels are Mature, indicating that angiogenesis is negligible. These results indicate that cabergoline significantly reduced the formation of new blood vessels (angiogenesis) in this model.

Figure 4 shows the results of a study of proliferation. Immunocytochemical study using antibody Ki-67 (that is, to analyze the degree of cell proliferation using antibodies against Ki-67) was used to assess the proliferative activity of implants using methods known in the art. Software for computing with images used for the calculation of Ki-67-positive cells and thus to calculate the proliferation index in each group. In foci in animals treated, caber is Olya (as in the low dose group, and in the high-dose group), observed a significant (p<0.001) decrease in proliferation compared with the control group.

The angiogenic status of foci were first analyzed using immunofluorescence assay using antibodies to identify new (vWF+/αSMA-) and old vessels (vWF+/αSMA+) and confocal microscopy (Leica Confocal Software). The immunofluorescence using antibodies developed against the background of the von Willebrand (vWF), present in endothelial cells and smooth muscle cells of blood vessels (α-SMA), can be used to study angiogenic actions Cb2. Blood vessels that are not newly formed, surrounded by a smooth muscle layer, giving them a maturity. Identification of endothelial cells was performed using vWF, whereas Mature vessels were identified by positive staining for α-SMA. Thus, vWF+/αSMA - blood vessels were seen as new or immature, while vWF+/αSMA+ vessels classified as old or Mature blood vessels.

In the control group implants had vysokokratnoy stroma and histological aspect of a complete reorganization and structure, usually observed in the focus of endometriosis, while implants in mice included in the groups of low and high doses, showed a loose stroma with loss of cellularity and er is anizatio, what is characteristic of atrophic/degenerative tissue. Morphometry showed no differences among groups in cell density, the ratio of stroma/gland and area glands.

TaqMan Real-time PCR and methods 2^-ΔΔCtused for analysis of gene expression profiles of three different markers that stimulate angiogenesis (VEGF, VEGFR-2, Notch-4), angiopoietin-1 (Ang-1), token antiangiogenesis, stimulating an increase of existing vessels and the resistance of the filter, and Wnt-1. Constitutive 18S ribosomal RNA (rRNA) was used to normalize the Ct values of the target gene. The Ct value in each group was expressed respect to the Ct values in the control group (calibrator) to calculate the relative expression method 2^-ΔΔCt. Complementary DNA (cDNA)derived from tumor cells of sarcoma 180 (S-180), and endothelial cells of the umbilical vein of a person (HUVEC) were used as negative and positive control, respectively, for gene expression of VEGF and VEGFR-2. The spleen was used as a positive control for Ang-1 and Wnt-1 and lung was used as a positive control for Notch-4.

Table 1 shows that the gene expression profiles of Pro-angiogenic markers (VEGF, VEGFR-2 and Notch-4) implants treated with low and high doses of cabergoline ("Cb2"), were reduced compared to controls. Ang1 and Wnt-1 is considered as angiogenic markers; profiles of their expression implants in mice treated with the low and high doses of Cb2, were increased compared to controls, showing that treatment with cabergoline associated with inhibition of angiogenesis. Data on the relative expression of the table is shown graphically in Figure 5.

Data are expressed as mean ± standard deviation (SD)

It was investigated the presence of dopamine receptors type 2 in human endometrial tissue and endometrial implants in women undergoing surgery (laparoscopy). TaqMan Real-time PCR and methods 2^-ΔΔCtused to confirm the presence of the dopamine receptor type 2 (Dp-r2","D2R") and VEGF in human endometrial tissue not only in the implants (Figa), but also in peritoneal endometriotic foci obtained from 10 women with laparoscopy (Figb, also including data no VEGF-R2). Positive and negative controls for Dp-r2 cDNA was HUVEC cells and S-180, respectively. For mice control Ct values was used as calibrator and human peritoneal lesions of Ct values HUVEC were used as calibrator to calculate the relative expression method 2^-ΔΔCt.

On Figa shows the presence of VEGF and Dp-r2 in endometrial implants animals in the three established groups. There was a trend to increased expression of Dp-r2, as the animals were treated with increasing doses of cabergoline. There is a tendency to decrease the expression of VEGF, as animals were treated with increasing doses of cabergoline.

On Figb shown (left column) relative expression of VEGF, VEGFR-2 (KDR) and D2R ("Dp-r2") in various types of endometriotic lesions; red, white and black. There is a clear difference in the expression of VEGF, VEGFR-2 and Dp-r2 according to the type of the hearth.

On Figb also shown (right column) relative expression of VEGF, VEGFR-2 (KDR) and D2R ("Dp-r2") in the endometrium. The relative expression of VEGF and VEGFR-2 in endometrial subjects with endometriosis is higher than that of subjects without endometriosis; the relative expression of Dp-r2 in the endometrium of subjects with endometriosis n the same than in subjects without endometriosis.

These results are shown in Table 2 below.

The results show that the dopamine agonist cabergoline, administered in doses of 0.05 and 0.1 mg/kg/day, was capable of:

(a) significantly reduce the number of active endometriotic lesions;

(b) to cause loss of cellularity and organizations in endometriotic implants, which represents a characteristic atrophic or degenerative tissue;

(C) significantly reduce the number of new blood vessels in endometriotic implants;

(d) significantly reduce the expression of markers of angiogenesis and cell proliferation and

(d) to enhance the degeneration of the tissues and reduce endometriotic implants.

There is a high degree of homology between VEGF humans and rodents, which indicates that the activity shown in the above-described model in rodents, applicable to human models. The results show that the introduction of a dopamine agonist has a significant effect on endometriosis, possibly associated with the effect on angiogenesis. These results can be related to the presence of dopamine receptors in ectopic and ectopic endometrial tissue.

Example 2

The composition is the form of tablets for oral administration represents 0.5 mg of cabergoline (commercially available under the name Dostinex®, Pfizer, Spain).

Other examples

Example A. the Patient with chronic pelvic pain undergoing diagnostic laparoscopy, and he diagnosed endometriosis type III. During the laparoscopy, the patient perform surgery, such as resection of accessible foci, and begin the introduction of cabergoline.

Example B. Previously, the patient was diagnosed with endometriosis, manifested symptoms of pelvic pain and dysmenorrhea. The introduction of cabergoline start without surgical intervention.

Example C. a Patient who has been diagnosed with endometriosis, treatment with GnRH agonists or danazol, or aromatase inhibitors) and begin the introduction of cabergoline (continuing use of the GnRH agonist) during a certain period. After the next 3 or 6 months in the absence of therapy, the patient is again treated by cabergoline for an additional period.

1. The use of a dopamine agonist in the manufacture of a medicinal product for the treatment or prevention of endometriosis.

2. The use according to claim 1, where the specified dopamine agonist is one of the amantadine, bromocriptine, cabergoline, chinagrid, e.g., pergolid, ropinirole and pramipexole.

3. The use according to claim 1, where the dopamine agonist is a cabergoline entered in the dose of 0.01-12.5 mg/week.

4. The use according to claim 1, where a is honest dopamine is chinagrid, injected dose at 25 ÷ 1000 mg/day.

5. The use according to claim 1, where the dopamine agonist is a parlodel entered in the dose 10-80 mg/day.

6. The use according to claim 1, where the dopamine agonist is administered for a period of from 1 day to 2 years.

7. The use according to claim 1, where the dopamine agonist is administered in combination with other surgical or medical treatment of endometriosis.

8. The use according to claim 1 or 2, where the agonist (agonist) dopamine is used to treat or prevent endometriosis in pregnant subject.

9. The use according to claim 1 or 2, which have a directional effect on the growth factor vascular endothelial (VEGF).

10. The use according to claim 1, which have a directional effect on the VEGF receptor type 2 (VEGFR-2).

11. The use according to claim 1, which have a directional effect on Notch-4.

12. The use according to claim 1, where the treatment or prevention of endometriosis is associated with a decrease in the number of endometrial glands.

13. The use according to claim 1, where the treatment or prevention of endometriosis is associated with a reduction (or removal) of the endometrial tissue is present outside the uterine cavity, and/or is a treatment for reducing and/or alleviating one or more symptoms associated with endometriosis.

14. The use according to claim 1, where the introduction of a dopamine agonist is orally and in the form of such compositions, the AK capsules, starch wafers, tablets, syrups, elixirs or cakes.