Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to medicaments for the treatment of endometriosis
• Endometriosis is a benign, chronic, gynaecological disease It may be defined as a presence of endometrial tissue, comprising both glandular epithelium and stroma, outside the uterine cavity It is a benign gynaecological disorder, which, in a sub-population of female patients, may develop into an aggressive disease Endometriosis is associated with various distressing symptoms including dysmenorrhoea, dyspareunia, pelvic pain and reduced fertility
• angiogenesis the process whereby new blood vessels are formed from pre-existing vessels
• vascular permeability factor/vascular endothelial growth factor VP/VEGF
• VP/VEGF vascular permeability factor/vascular endothelial growth factor
• the potential effectiveness of anti-angiogenic therapy for treating endometriosis has been assessed using a study using human endometrial tissues transplanted to immuno-compromised nude mice
• Four different anti-angiogenic agents were administered three weeks after the endometrial explants had been transplanted (Nap et a/, 2004) All four inhibitors were able to reduce the size of established explants, and new blood vessel formation was stopped
• the known anti-angiogenic agents are highly toxic, and rather difficult to introduce in a human clinical setting
• compositions which include a dopamine agonist may be used to treat endometriosis
• the present invention therefore provides the use of a dopamine agonist in the manufacture of a medicament for the treatment and/or prevention of endometriosis
• the present invention also provides the use of a dopamine agonist in the treatment and/or prevention of endometriosis
• treatment of endometriosis includes treatment to reduce (or remove) the amount of endometrial tissue which is present outside the uterine cavity (e g reduction or removal of endometriotic lesions) and/or treatment to reduce and/or ameliorate one or more symptoms associated with endometriosis (e g treatment to ameliorate and/or reduce the symptoms of dysmenorrhoea, treatment to ameliorate and/or reduce the symptoms of dyspareunia, and/or treatment to ameliorate and/or reduce pelvic pain)
• treatment of endometriosis includes treatment to reduce the number of instances, and/or reduce the size of instances, of endometrial tissue which is present outside the uterine cavity (e g reduction of number and/or
• endometriosis includes, for example, peritoneal endometriosis, ovarian endometriosis and deep endometriosis.
• dopamine agonist means a compound that acts like dopamine, for example, a drug which interacts (e g binds specifically) with a dopamine receptor to mimic a dopamine action It does not include compounds which are exclusively "dopaminergic substances", i e exclusively compounds which, through different mechanisms of action, increase the levels of dopamine
• dopamine agonist does not include the bridged indenopyrrolocarbazoles disclosed in US 6359130
• Dopamine agonists have previously been found to be useful in the treatment or prevention of ovarian hyperstimulation syndrome (OHSS) (WO
• Dopamine agonists within the terms of the invention include, but are not limited to, amantadine, bromocryptine, cabergoline, quinagolide, lisunde, pergolide, ropinirole and pramipexole
• a preferred dopamine agonist for use in the present invention is cabergoline.
• a preferred dopamine agonist for use in the present invention is quinagolide
• the so-called "partial dopamine agonists" (e g tergu ⁇ de) may also be used in accordance with the invention However, the use of dopamine agonists is preferred
• a single dopamine agonist is used
• the dopamine agonist may be administered at a dose (e g an oral dose to a human patient) of between 25 micrograms per day and 80 mg/day, preferably between 50 micrograms per day and 5 mg/day, more preferably between 300 micrograms per day and 1 mg/day, suitable doses within this range depend to the dopamine agonist to be used, as is readily apparent to those skilled in the art
• the dopamine agonist is cabergoline
• the cabergoline is administered at a dose (e g an oral dose to a human patient) of between 0 01 and 12 5 mg/week, preferably between 0 1 and 10 mg/week, more preferably between 0 5mg and 5 mg/week, more preferably at a dose of between 3 5 mg/week and 4 mg/week
• the dopamine agonist may be administered as, for example, a single daily dose (of for example, between 0 1 mg/day and 5mg/day, from 0 2 mg/day to 1 mg/day, for example 0 5 mg/day), or the daily dose may be divided into two or more sub-doses to be taken at different times over a 24 hour period
• the dopamine agonist (cabergoline) may be administered as a daily dose at the levels above, or as equivalent doses e g per week, twice a week, or every two days In one regime, the dopamine agonist (for example, cabergoline) is
• the dopamine agonist is quinagolide
• the quinagolide is administered at a dose (e g an oral dose to a human patient) of between 25 and 1000 micrograms/day, preferably between 25 and 500 micrograms/day, more preferably between 25 and 300 micrograms/day
• the dopamine agonist may be administered as, for example, a single daily dose, or the daily dose may be divided into two or more sub-doses to be taken at different times over a 24 hour period
• the dopamine agonist (quinagolide) may be administered as a daily dose at the levels above, or as equivalent doses e g per week, twice a week, or every two days
• the dopamine agonist is bromocryptine
• the bromocryptine is administered at a dose (e g an oral dose to a human patient) of between 10 to 80 micrograms/day, preferably 10 to 40 mg/day
• the dopamine agonist is used as the only medical treatment for endometriosis
• the dopamine agonist may be used in the absence of other medical or surgical treatments [for example, in the absence of danazol]
• administration of a dopamine agonist may be combined with other medical or surgical treatments for endometriosis [for example, NSAIDs and/or hormonal treatments (danazol, OCs, medroxyprogesterone acetate, other progestins, GnRH agonists and antagonists, aromatase inhibitors)]
• other medical or surgical treatments for endometriosis for example, NSAIDs and/or hormonal treatments (danazol, OCs, medroxyprogesterone acetate, other progestins, GnRH agonists and antagonists, aromatase inhibitors)
• surgical treatment or medical treatment may be used prior, during or after treatment with dopamine agonist
• dopamine agonist may provide substantial clinical benefits such as, for example significant decrease in the percentage of active endometriotic lesions, significant loss of the cellularity and organisation manifesting characteristics of atrophic or degenerative tissue in endometriotic lesions, and significant decrease in the number of new blood vessels in endometriotic lesions
• the dopamine agonist for example, cabergoline
• the dopamine agonist may be administered for long periods of time (e g 1 to 3 weeks (e g 1 to 21 days, for example 1 to 14 days), from 1 day to 3 months, 1 day to six months, 1 day to 12 months, or 1 day to 2 years, or longer) with therapeutically beneficial effect, and low risk of side effects
• the administration may be continuous at e g daily or weekly dose, or may be interrupted by one or more interruptions of, for example, a number (e g 1 to 3) of weeks or a number (e g 1 to 3) of months
• the dopamine agonist may be administered for as long as pain (or other symptom) continues
• the dopamine agonist for example, cabergoline, quinagolide
• the dopamine agonist may be administered to a pregnant subject
• the treatment or prevention of endometriosis may be associated with a decrease in the amount of endometrial glands
• vascular endothelial growth factor may be targeted by the dopamine agonist, as a factor in the development of endometriosis
• the isoforms VEGF 121 and VEGF 165 appear to be mainly involved in the process of angiogenesis (Watkins, R H , et al , Am J Physiol 1999, vol 276, pp 858-67)
• Two specific endothelial cell membrane receptors for VEGF have been identified, VEGF rece ⁇ tor-1 (VEGFR-1 , Flt-1) and VEGFR-2 (FIk- 1/KDR)
• VEGFR-2 appears to be mainly involved in regulating angiogenesis and vasculogenesis
• VEGFR-2 (KDR) may thus be targeted by the dopamine agonist, as a factor in the development of endometriosis
• Notch-4 may be targeted by the dopamine agonist, as a factor in the development of endometriosis VEGF
• VEGFR-2 and Notch-4 may be targeted by the dopamine agonist, as a factor in the development of endometriosis
• Other mechanisms of action of the dopamine agonist are within the scope of the invention
• the dopamine agonist is administered as a pharmaceutically acceptable preparation
• Preparations may be administered in accordance with the invention in pharmaceutically acceptable compositions that may optionally comprise pharmaceutically acceptable salts, buffering agents, preservatives and excipients
• Pharmaceutical preparations which include dopamine agon ⁇ st(s) as active agents are well known in the art and are commercially available
• cabergoline is available under the registered trade marks Cabaser and Sogilen/Dostinex
• the use of such commercially available dopamine agonist preparations in the treatment of endometriosis is according to the invention
• the mode of administration selected will depend on the acuteness and severity of the condition being treated, and the dosage required Any mode of administration that produces desired therapeutic effect without unacceptable adverse effects is relevant in practicing the invention
• Such modes of administration may include oral, rectal, topical, transdermal, sublingual, intramuscular, parenteral, intravenous, intracavity, vaginal, and adhesive matrix to be used during surgery
• Various approaches for formulating compositions for use in accordance with the invention are described in the Handbook of Pharmaceutical Excipients, Third Edition, American Pharmaceutical Association, USA and Pharmaceutical Press UK (2000), and Pharmaceutics - The Science of Dosage Form Design, Churchill Livingston (1988)
• the administration is oral Compositions suitable for oral administration include capsules, cachets, tablets, syrups, elixirs or lozenges
• a method of treatment or prevention of endometriosis comprising a step of administration to a patient in need thereof of a dopamine agonist
• the dopamine agonist is administered in the form of a pharmaceutical preparation which includes one or more dopamine agonists as the active ingredient
• the dopamine agonist may be administered at a dose (e g an oral dose to a human patient) of between 25 micrograms per day and 80 mg/day, preferably between 50 micrograms per day and 5 mg/day, more preferably between 300 micrograms per day and 1 mg/day, suitable doses within this range depend to the dopamine agonist to be used, as is readily apparent to those skilled in the art
• the dopamine agonist is cabergoline
• the cabergoline is administered at a dose (e g an oral dose to a human patient) of between 0 01 and 12 5 mg/week, preferably between 0 1 and 10 mg/week, more preferably between 0 5mg and 5 mg/week, more preferably at a dose of between 3 5 mg/week and 4 mg/week
• the dopamine agonist may be administered as, for example, a single daily dose (of for example, between 0 1 mg/day and 5mg/day, from 0 2 mg/day to 1 mg/day, for example
• the dopamine agonist is quinagolide
• the quinagolide is administered at a dose (e g an oral dose to a human patient) of between 25 and 1000 micrograms/day, preferably between 25 and 500 micrograms/day, more preferably between 25 and 300 micrograms/day
• the dopamine agonist may be administered as, for example, a single daily dose, or the daily dose may be divided into two or more sub-doses to be taken at different times over a 24 hour period
• the dopamine agonist (quinagolide) may be administered as a daily dose at the levels above, or as equivalent doses e g per week, twice a week, or every two days
• the dopamine agonist is bromocryptine
• a dose e g an oral dose to a human patient
• a dose e g an oral dose to a human patient
• a dopamine agonist may be combined with other medical or surgical treatments for endometriosis [for example, NSAIDs and/or hormonal treatments (danazol, OCs, medroxyprogesterone acetate, other progestins, GnRH agonists and antagonists, aromatase inhibitors)]
• surgical treatment or medical treatment may be used prior, during or after treatment with dopamine agonist
• the dopamine agonist for example, cabergoline
• the dopamine agonist may be administered for long periods of time (e g 1 to 3 weeks (e g 1 to 21 days, for example 1 to 14 days), from 1 day to 3 months, 1 day to six months, 1 day to 12 months, or 1 day to 2 years, or longer) with therapeutically beneficial effect, and low risk of side effects
• the administration may be continuous at e g daily or weekly dose, or may be interrupted by one or more interruptions of, for example, a number (e g 1 to 3) of weeks or a number (e
• the patient may be pregnant
• the treatment or prevention of endometriosis may be associated with a decrease in the amount of endometrial glands
• FIGURE 1 shows the percentage of active lesions following the animal study discussed below, for the control group, and the groups treated with low dose (0 05 mg/kg/day) and high dose (0 1 mg/kg/day) of cabergoline
• FIGURE 1 a shows the glands/stroma ratio in the three established groups [both low and high cabergoline ("Cb2") doses had more stroma and less glands than the controls ( * P ⁇ 0 05)]
• FIGURE 2 shows the blood vessels (mm 3 ) for the control and low and high dose groups
• FIGURE 3 shows the percentage of “mature” and “newly formed” blood vessels in the animals of the control, low and high dose groups
• FIGURE 4 shows the Proliferation Index for the control and low and high dose groups
• FIGURE 5 shows the relative expression of VEGF, VEGFR-2 (KDR), Notch-4, Ang 1 and Wnt-1 for the control, low and high dose groups
• FIGURE 6a shows the presence of dopamine receptor 2 (Dp-r2) and VEGF in endometrial implants of the animals in the three established groups (control, low and high dose groups)
• FIGURE 6b shows the relative expression of VEGF, VEGFR-2 (KDR) and D2R in endometriotic lesions (left-hand column) and in the endometrium (right- hand column)
• mice Female mice (Hsd Athimic Nude- nu, Harlan lberica S L, Barcelona, Spain) were individually housed in autoclaved cages and bedding, in laminar flow filtered hoods The animal room was maintained at 26 C with a 12-h light, 12-h dark cycle, and mice were fed ad libitum with autoclaved laboratory rodent chow and acidified water All handling was performed in laminar flow filtered hoods
• a mixture of ketamine/medetomidine 75 ⁇ g/g ketamine and 1 ⁇ g/g medetomidine) (Ketolar ® , Parke-Davis, Espa ⁇ a, Domtor®, Pfizer, Spam) i p injected, was used to anesthetize mice before invasive procedures and atipamezole (Antisedan®, SmithKline Beecham, Spain) 1 ⁇ g/g i
• 17 ⁇ -estrad ⁇ ol (Innovative Research of America, Sarasota, FL) were placed sc in the neck of each animal According to the manufacturer's information, capsules provide continuous release of hormone at serum concentrations of 150-250 pmol/liter, in the range of physiological levels in mice during the estrous cycle This stable physiological level of estrogen promotes the growth of transplanted human endometrium and avoids intermouse differences related to various stages of the estrous cycle
• TEM Optical microscopy
• TEM transmission electron microscopy
• morphometry was performed to ascertain the presence of endometrial glands and stroma and study subcellular ultrastructural changes, area of the implants and cellular density
• TaqMan Real-time PCR and 2 ⁇ CI methods were used to analyze the gene expression profiles of three different markers that promote angiogenesis (VEGF, VEGFR-2, Notch-4), Ang ⁇ opo ⁇ et ⁇ n-1 (Ang-1 ), an antiangiogenesis marker which promotes the enlargement of existing vessels and resistance to leakage, and Wnt-1 Demonstration of the presence of the VEGF and dopamine type 2 receptor (Dp-r2) expression in experimental implants, human peritoneal endometriotic lesions, and endometrium, was conducted using the TaqMan Realtime PCR and 2 ⁇ CI method (Fig 6a, 6b) Similarly, this method was used to demonstrate the presence of VEGFR-2 expression in human peritoneal endometriotic lesions, and endometrium (Fig 6b)
• the animals treated with cabergoline both low and high dose groups
• treatment with cabergoline appears to reduce the number of active endometriotic lesions in this model
• the OM and TEM studies showed that in the control group the endometriotic lesions presented a high cellular stroma and a histological aspect of complete reorganization and structure, as may be seen in a typical human endometriosis lesion
• treated lesions high and low dose of cabergoline
• Figure 2 shows the blood vessels (mm 3 ) for the control, low and high dosage groups, divided between "mature” blood vessels and "newly formed” blood vessels
• the control group has a greater proportion of newly formed blood vessels (indicative of significant angiogenesis), while the low and high dose groups have a significantly greater proportion of mature blood vessels, suggestive of significantly reduced angiogenesis This was also demonstrated by histology (results not shown) These results indicate that the cabergoline significantly reduced new blood vessel formation (angiogenisis), in this model
• Figure 3 shows the percentage of blood vessels in the control and low and high dosage groups
• the control group has approximately 74% of the total blood vessels as newly formed blood vessels, indicating significant angiogenisis
• the low and high dosage groups on the other hand, have approximately 85 to 89% of the total as mature blood vessels, indicating that angiogenisis is not significant
• Figure 4 shows the results of a proliferation study
• An immunocyto chemistry study using the K ⁇ -67 antibody ( ⁇ e analysing the degree of cellular proliferation employing antibodies against K ⁇ -67) was used to evaluate the proliferative activity of the implants using methods known in the art
• Image counting software was used to count the K ⁇ -67 positive cells and hence calculate the proliferation index in each group
• a significant (P ⁇ 0 001) decrease in proliferation was observed in lesions in animals treated with cabergoline (both low and high dose groups) compared with the control group
• angiogenic status of the lesions was initially analyzed using immunofluorescence employing antibodies to identify new (vWF+/ ⁇ SMA-) and old vessels (vWF+/ ⁇ SMA+) and confocal microscopy (Leica Confocal Software) Immunofluorescence employing antibodies raised against the Von Willebrand factor (vWF) present in endothelial cells and vascular smooth muscle cells ( ⁇ - SMA) can be used to test the antiangiogenic action Cb2 Blood vessel which are not of new formation, are rounded by a smooth muscle layer which confers maturity to them Identification of endothelial cells was made employing vWF, whereas mature vessels were identified by ⁇ -SMA positive staining Thus, vWF+ / ⁇ SMA- blood vessels were considered new or immature, while vWF+ / ⁇ SMA+ vessels were classified as old or mature blood vessels
• TaqMan Real-time PCR and 2 ⁇ °' methods were used to analyze the gene expression profiles of three different markers that promote angiogenesis (VEGF, VEGFR-2, Notch-4), Ang ⁇ opo ⁇ et ⁇ n-1 (Ang-1), an antiangiogenesis marker which promotes the enlargement of existing vessels and resistance to leakage, and Wnt-1
• the housekeeping 18S rRNA was used to normalize the target gene Ct values
• the Ct value in each group was expressed relative to the control group Ct values (calibrator), to calculate the relative expression by the 2 ⁇ CI method cDNA obtained from sarcoma 180 tumor cells (S-180) and human umbilical vein endothelial cells (HUVEC) was used as negative and positive control, respectively, for the VEGF and VEGFR-2 gene expression
• Spleen was used as positive control for Ang-1 and Wnt-1
• lung was employed as a Notch-4 positive control
• Table 1 shows that the gene expression profiles of pro-angiogenic markers (VE
• HUVEC and S-180 cDNA cells were 10 HUVEC and S-180 cDNA cells, respectively.
• control Ct values were used as a calibrator, and in human peritoneal lesions the HUVEC Ct values were employed as calibrator to calculate the relative expression by 2 " ⁇ CI method.
• Figure 6a shows the presence of VEGF and Dp-r2 in endometrial implants of the animals in the three established groups. There was a trend
• FIG. 6b shows (left-hand column) the relative expression of VEGF, VEGFR-2 (KDR) and D2R ("Dp-r2") in different types of endomet ⁇ otic lesions, red, white and black
• Dp-r2 D2R
• VEGF, VEGFR-2 (KDR) and D2R in the endometrium
• KDR KDR
• D2R D2R
• results indicate that administration of dopamine agonists has a significant effect on endometriosis, possibly linked to action on angiogenesis
• results may be related to the presence of dopamine receptors in eutopic and ectopic endometrial tissue
• a formulation as a tablet for oral use is 0 5 mg of cabergoline
• Example A A patient undergoes diagnostic laparoscopy after suffering chronic pelvic pain and is diagnosed with endometriosis type III At the same laparoscopy, the patient undergoes surgery such as resection of available lesions and administration of cabergoline is initiated
• Example B Patient diagnosed previously of endometriosis, presenting with symptoms of pelvic pain and dysmenorrhea Administration of cabergoline is initiated without surgery
• Example C Patient diagnosed with endometriosis undergoing treatment with GnRH agonists (or danazol or aromatase inhibitors) and administration of cabergoline is initiated (with continued use of GnRH agonist) for a period After a further 3 or 6 months of no therapy, patient restarts cabergoline for a further period

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