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HK1049117A1 - Method for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction - Google Patents

Method for the therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction Download PDF

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HK1049117A1
HK1049117A1 HK03101215.4A HK03101215A HK1049117A1 HK 1049117 A1 HK1049117 A1 HK 1049117A1 HK 03101215 A HK03101215 A HK 03101215A HK 1049117 A1 HK1049117 A1 HK 1049117A1
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antagonist
administered
treatment
short
lhrh antagonist
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J‧恩格尔
J‧恩格爾
H‧利瑟穆勒-温赞
R‧费尔比尔保穆
H‧利瑟穆勒-溫贊
K‧狄德里啻
W‧库皮克尔
R‧費爾比爾保穆
W‧庫皮克爾
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赞塔里斯有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
    • A61P15/06—Antiabortive agents; Labour repressants
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

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  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Reproductive Health (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

The present invention provides a method for therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction by short term induction treatment with an LH-RH antagonist for 4 to 12 weeks. According to another aspect of the present invention, the short term LH-RH treatment is followed by the combined or separate administration of one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof. According to a further aspect of the present invention a pharmaceutical composition comprising an LHRH antagonist and one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgetic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combinations thereof are provided.

Description

Method for treating extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction
no marking
Field of the invention
Endometriosis is one of the most common pathologies in the diagnosis of gynaecological patients. For example, 10% to 25% of women with gynecological symptoms in the uk and usa suffer from this disease. Clinical diagnosis is usually performed by laparoscopic observation of bleeding or fibrotic lesions of pelvic organs. Ectopic endometrial tissue changes cyclically with ovarian hormones. Periodic bleeding from endometrial deposits contributes to local inflammatory responses. Endometriosis usually occurs in women of childbearing age with a prevalence of at least 1% (see Shaw, R.W (1993), The endometriosis map (An Atlas of endometrisis, The Parthenon Publishing Group).
Endometriosis is generally divided into endometriosis in the uterus (adenomyosis), endometriosis outside the uterus and endometriosis outside the reproductive organs.
Chronic pelvic pain can occur in association with endometriosis or as an independent disease.
Fallopian Tube Obstruction (FTO) is a more common condition that can account for 20% of fallopian tube infertility cases (see Winfield, A.C., et al, significant angle occlusion in utero-salpingography: by glucagon Reversal (applied coronary occlusion in systemic glycation), J.X.X.X.J. Roentgeno 1982; 139: 525-527). Background information and prior art
Sampson proposed: reflux of menses and subsequent implantation of endometrial tissue on the Peritoneal surface results in endometriosis [ Sampson, J.A. (1927), endometriosis in the peritoneum resulting from the dissemination of menses of endometrial tissue into the Peritoneal cavity [ maternal endometrological device of intraperitonal tissue in the Peritoneal cavity ] journal of gynecologic sciences in the united states (am.j.
The pathogenesis of endometriosis can be linked to several etiological factors:
dwowski et al propose: genetic and immunological factors contribute to endometriosis [ Dwowski, W.P., Steele, R.W. and Baker, G.F. (1981), cellular immunodeficiency in endometriosis (scientific immunity in endometeriosis), J.Dow.Sci.USA (am.J.Obstet. Gyneo.), 141, 377 ].
Distal embolization of blood and lymphatic vessels has demonstrated and explained the (rare) finding of endometriosis outside the peritoneal cavity, e.g. skin, lungs and kidneys.
The cells arranged on the Mullerian tube arise from primitive cells that differentiate into peritoneal cells and cells located on the surface of the ovary. It has been proposed that: these mature cells undergo de-differentiation (de-differentiation) back to their original origin and then transformed into endometrial cells [ levender, g. (1941), by induced osteogenesis (Bone formation byindication), an.
There are reports that: dysmenorrhea, acute or chronic pelvic pain, dyspareunia and infertility are the most common clinical symptoms.
FTO represents a heterogeneous group of pathologies derived from the basis of preliminary internal occlusion or external compression of estrogen-sensitive diseases, such as endometriosis, adenomyosis, tubal endometriosis and myoma. In addition to laparoscopy, FTO is also often diagnosed by hysterosalpingography.
The first choice of treatment involves laparoscopic removal of the endometrial lesions. This step may be followed by treatment with danazol or an LHRH agonist (6 months). Women receiving danazol therapy may suffer from gastrointestinal and liver diseases as well as severe side effects that are male-characteristic.
It has also been proposed from a theoretical point of view: treatment of endometriosis and uterine fibroids by immediate inhibition of LHRH antagonists is applied to shorten the treatment time and accelerate the improvement of subjective symptoms [ Th.Reissmann et al, Human journal of reproduction (Human reproduction), Vol.10, No. 8, pp.1974-1981, (1995) ].
Furthermore, Hodgen, in us patent 5,658,884, teaches a regimen for treating gonadal-dependent disorders by reducing estrogen supply by chronically administering a GnRH antagonist for 6 months or more at a dosage effective to inhibit proliferation of endometrial tissue without substantially stopping endogenous estrogen production. For this purpose, Hodgen teaches a regimen or dosage of GnRH antagonist to achieve 24 hour serum estradiol levels in the range of about 25 to 50pg/ml, preferably about 35 to 45 pg/ml. However, Hodgen does not describe estradiol serum levels that fluctuate between 50 and 75 pg/ml. Furthermore, Hodgen in us patent 5,658,884 teaches only a continuous long-term treatment (on a daily or periodic basis, the latter meaning weekly or monthly administration), and does not teach only a short-term induction treatment of 4 to 12 weeks. Furthermore, Hodgen does not describe any combination therapy involving a GnRH antagonist in the treatment of endometriosis. This treatment is described only in monkeys, but also includes expensive and repeated progesterone challenge experiments to provide 24 hour mean serum estradiol levels of 30 to 50 pg/ml.
The result of the abrupt functioning of LHRH-competitive therapy is that exacerbations of symptoms may occur on certain days. Subsequent prolonged treatment is required to avoid the occurrence of endometrial tissue re-proliferation, hormone withdrawal symptoms and bone demineralization.
Therefore, an effective drug therapy should immediately reduce the residual extrauterine endometrial tissue present after laparoscopic surgery. The treatment period should be only 4 to 12 weeks without any major symptoms of hormone withdrawal or ovarian cyst formation.
LHRH antagonists produce an immediate start of hormonal suppression and thus a reduction in benign gynaecological tumours, such as uterine fibroids, within a short time [ human journal of reproduction (humanreproduction) 1998, 13 ]. Objects of the invention
The present invention relates to an improvement in the medical treatment of extrauterine proliferation of endometrial tissue by administration of an LHRH antagonist to a patient having clinical symptoms of endometriosis, the improvement consisting of: immediate reduction of ectopic endometrial tissue immediately stops symptoms such as severe pain, chronic pelvic pain, and dysmenorrhea preventing any progression of the disease from hormone withdrawal symptoms preventing ovarian cyst formation, bone demineralization, and gastrointestinal or liver disease
The drug therapy of the invention may be initiated early to mid follicular phase, preferably on days 1 to 3 of the cycle. The serum concentration level of estradiol is kept between 35 and 80pg/ml, preferably between about 45 and 75pg/ml, particularly preferably between about 50 and 75pg/ml during the treatment. The LHRH antagonist is administered for only 4 to 12 weeks (short induction therapy), either daily, weekly or monthly. In accordance with the present invention, following short-term induction therapy, a contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone, or any combination thereof is administered.
Summary of the invention
In the treatment of extrauterine endometrial tissue with LHRH antagonists, treatment begins on days 1 to 3 of the menstrual cycle. Before starting the treatment with LHRH antagonist, the diagnosis is performed laparoscopically.
In cases of severe pain, LHRH antagonist therapy can be started without first laparoscopy.
Treatment will continue until clinical symptoms disappear and no endometrial hyperplasia is seen. No further endometrial hyperplasia occurs due to the immediate onset of suppression by the gonadotropins LH and FSH and the sex steroids estradiol and progesterone. Benign tumors or other sex steroid dependent lesions like endometriosis were reduced in 4 to 12 weeks of treatment. No ovarian cysts are formed because they do not act suddenly.
Moreover, when the estradiol value is maintained in the range of 35 to 80pg/ml, preferably about 45 to 75pg/ml, particularly preferably about 50 to 75pg/ml, of the early follicular phase and is not further increased or decreased, no hormone withdrawal symptoms are seen. There is no need to titrate the dosage of LHRH antagonist, for example by performing expensive progesterone challenge experiments.
In a method of treating extrauterine proliferation of endometrial tissue, the improvement comprising, in accordance with the present invention: immediate reduction of ectopic endometrial tissue to prevent any progression of disease and avoidance of hormone withdrawal symptoms prevent ovarian cyst formation, bone demineralization, and gastrointestinal or hepatic disease
Drug treatment is initiated on days 1 to 3 of the cycle and estradiol levels are maintained at early follicular phase values throughout the treatment period by administration of an LHRH antagonist, preferably cetrorelix, teverelix, ganirelix, antide or abarelix. The antagonist may also be the LHRH antagonist D-63153(Ac-D-Nal-D-pCl-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2) as described in German patent application Specification 19911771.3, 3/11/1999.
The LHRH antagonist may be administered at a weekly dose of 3 to 10 mg/week for 4 to 12 weeks, or at a daily dose of 0.25 to 0.5 mg/day for 4 to 12 weeks.
The LHRH antagonist may also be administered at a monthly dose of 12 to 40 mg/month for 4 to 12 weeks.
In one repeat treatment the LHRH antagonist can be administered for 4 to 12 weeks and this treatment is repeated 2 or 3 times a year, so that a repeat treatment cannot be directly followed after a short induction treatment. Typically there is a period of weeks or months after the end of the short induction treatment and before the start of the repeat treatment, during which no LHRH antagonist is administered.
To demonstrate the feasibility of maintaining low estradiol secretion under modulated LHRH-antagonist treatment to allow therapeutic inhibition to occur without withdrawal symptoms, 9 patients who were confirmed to have endometriosis were treated with 3mg cetrorelix acetate administered subcutaneously weekly for 8 weeks. The patient's compliance is excellent, avoiding any hot flashes or other withdrawal symptoms, and the mean estradiol serum concentration fluctuates between 37pg/ml and 64pg/ml, preferably between 45-75pg/ml, particularly preferably between about 50-75pg/ml, as confirmed by a second laparoscopy without any progression of the disease. Histological biopsy revealed: at the end of the treatment, there was no endometrial hyperplasia. No ovarian cyst formation was found.
Figure 1 shows the continuous inhibition of estradiol levels to early follicular phase values (35pg/ml to 80pg/ml, preferably 45-75pg/ml, particularly preferably about 50-75pg/ml) obtained from endometriosis patients treated for 8 weeks with a 3mg week dose of cetrorelix (LHRH antagonist). At the end of the treatment, an immediate and continuous inhibition of estradiol levels was obtained, without any signs of estradiol withdrawal symptoms and endometrial hyperplasia.
Figure 2 shows the serum levels of estradiol following administration of cetrorelix at weekly doses of 1mg and 3mg once a week, respectively. Serum levels of estradiol are between about 35pg/ml and 80pg/ml, preferably between about 45-75pg/ml, and particularly preferably between about 50-75 pg/ml.
Endometriosis patients with the unique symptoms of pain are suffering from a chronic disease. Surgical approaches in the sense of curative therapy and drug treatments that inhibit sex steroid secretion in patients often only bring about temporary improvements. The rate of relapse of discomfort is very high, approximately 70% within 5 years of ending treatment (Schweppe, 1999).
At the same time, fundamental surgical therapies and inhibition of estrogen secretion bring about considerable side effects. Radical surgical therapy in the sense of hysterectomy with bilateral adnexal resection is not suitable therapy for young, premenopausal women. Chronic deficiency of estrogen will lead to the following autonomic (vegetative) symptoms: hot flashes, sweating, vaginal dryness, feeling depressed, and the risk of osteoporosis. Replacement therapy with the synthetic steroid danazol can cause andropathies due to the effects that produce male characteristics.
The aim of the medical treatment of patients with symptomatic endometriosis is to obtain a treatment which is free from side effects, in particular avoids the negative effects of estrogen inhibition, and which is effective for a long time after the end of the treatment. This particular pharmacological profile of action of LHRH antagonists offers new possibilities for the treatment of endometriosis.
In a suitable dose, e.g. 3mg ceftotideSubcutaneous/weekly, weekly administration of LHRH antagonists for 8 weeks can result in inhibition of estrogen secretion control such that a resulting serum concentration of between about 35pg/ml and 80pg/ml, preferably about 45-75pg/ml, and particularly preferably about 50-75pg/ml is obtained. Within this serum concentration range, no autonomic symptoms occurred. Can also avoid the development of osteoporosis. Symptomatic pain will be effectively inhibited during all stages of the disease (rAFS I-IV). Clinical regression of the disease in the sense of a reduction in the area of implantation was noted during the rAFS I-II phase (Felberbaum et al, 2000).
In a preferred embodiment of the invention, after 8 to 12 weeks of such treatment, the patient may take a contraceptive, preferably an oral contraceptive, more preferably an oral contraceptive with a progestogenic component, unless pregnancy is desired. Among these combinations, mention must be made of 2mg and 0.04mg of lineestrol or 2.5mg and 0.05mg of lineestrol (for example Yermonil)、Lyn-ratiopharm-Sequenz) In combination of (1).
After short-term induction therapy with LHRH antagonists alone or in combination with steroidal antirheumatic and/or analgesic agents, combination therapy with androgens other than 17-alpha-alkyl substituted testosterone, such as danazol, may also be used. An example of a suitable androgen is halotestinTM(Fluoromethyltestosterone).
The treatment with a contraceptive, preferably an oral contraceptive, preferably with a progestagen therein, should be continued individually until a typical pain sensation occurs. Due to the effect of the progestogenic component of such a contraceptive, preferably an oral contraceptive, the patient will experience relatively little menstrual bleeding at this stage.Furthermore, to overcome the particularly severe pre-and peri-menstrual pain sensations, concomitant drugs with suitable non-steroidal antirheumatic drugs such as diclofenac, ibuprofen, indomethacin, oxicam derivatives or aspirin may be administered at this stage. Analgesics such as flupirtine maleat (Katadolon) may also be administered)。
If further pain symptoms are present during the treatment with the progestogenic contraceptive, preferably an oral contraceptive, the daily, weekly or monthly treatment with appropriate doses of LHRH antagonist as described above may be repeated. Details regarding the corresponding treatment options are given below. If the patient is completely pain free, the treatment may be changed to a progestagenic contraceptive, preferably an oral contraceptive, administered in combination with a suitable non-steroidal anti-rheumatic or analgesic as concomitant medication.
This therapy with intermittent administration of LHRH antagonists brings about a new and innovative unlimited treatment without side effects and this treatment significantly reduces the treatment costs for the patient. Pharmaceutical formulations suitable for therapy
Pharmaceutical formulations of LHRH antagonists suitable for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and Fallopian Tube Obstruction (FTO) may be, for example
a) Acetate salt formulation having a concentration of 1mg/1ml or less, wherein the powder is soluble in water for injection (Wfl) or Gluconic Acid (GA);
b) acetate salt formulations at concentrations of 1.5mg/1ml to 5.0mg/1ml, preferably 2.5mg/1ml, wherein the powder may be dissolved in water for injection (Wfl) or Gluconic Acid (GA);
c) acetate salt formulations at concentrations of 10mg/1ml to 30mg/1ml, preferably 15mg/1ml, wherein the lyophilized powder may be dissolved in Gluconic Acid (GA) or water for injection (Wfl).
In accordance with one aspect of the present invention, in a method of treating extrauterine proliferation of endometrial tissue, chronic pelvic pain, and/or Fallopian Tube Obstruction (FTO), the improvement provided is: the LHRH antagonist is administered to a patient in need of such treatment as short-term induction therapy for about 4 to 12 weeks, and then administration of the LHRH antagonist is discontinued.
The meaning of a short induction treatment time of about 4 to 12 weeks is: the treatment period is between about 28 to about 84 days, or from about 1 month to about 3 months.
According to another aspect of the invention, in the method as described above, the improvement is provided wherein the LHRH antagonist is administered such that the serum level of estrogen is between about 35pg/ml and 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: following short-term induction treatment with an LHRH antagonist, a contraceptive, preferably an oral contraceptive, is administered.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: following short-term induction therapy with LHRH antagonists, a non-steroidal anti-rheumatic agent is administered.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: wherein the short-term induction therapy with the LHRH antagonist is followed by administration of an analgesic.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: after short-term induction treatment with an LHRH antagonist, androgens other than 17-alpha-alkyl substituted testosterone are administered.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: after short-term induction treatment with an LHRH antagonist, one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone or any combination thereof are administered in combination or separately.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: the LHRH antagonist is administered starting at the early to middle of the follicular phase, preferably on days 1 to 3 of the cycle.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
According to another aspect of the invention, in the improved method as described above, the improvement is characterized by: the LHRH antagonist is administered in a weekly dose of 3 to 10 mg/week during a period of 4 to 12 weeks of short-term induction therapy.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: the LHRH antagonist is administered at a daily dose of 0.25 to 0.5 mg/day during a period of 4 to 12 weeks of short-term induction treatment.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: the LHRH antagonist is administered at a monthly dose of 12 to 40 mg/month during a short induction treatment period of 4 to 12 weeks.
According to another aspect of the invention, in the method as described above, there is provided an improvement characterized in that: the LHRH antagonist is administered for induction treatment for 4 to 12 weeks and this treatment is repeated 2 or 3 times a year.
According to a further aspect of the present invention there is provided a pharmaceutical composition for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), comprising an LHRH antagonist and optionally one or more components selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof, and optionally pharmaceutically acceptable excipients, whereby, the LH-RH antagonist is administered to a patient in need thereof for about 4 to 12 weeks of short-term induction therapy, administration of the LH-RH antagonist is then discontinued and the patient is optionally administered, together or separately, one or more ingredients selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than 17-alpha-alkyl substituted testosterone, or any combination thereof.
Suitable excipients and dosage forms are described, for example, by k.h.bauer, k.h.fr * mming and C.F * hrer, in Lehrbuch der Pharmazeutischen technology, 6 th edition, Stuttgart 1999, pages 163-186 (excipients) and pages 227-386 (dosage forms), including the references cited therein.
The LH-RH antagonist may be administered, for example, subcutaneously (s.c.), intramuscularly (i.m.), or by inhalation. The ingredient selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof may be administered in a manner known in the art (see e.g. german, european or us pharmacopoeias), preferably orally or by inhalation.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered such that the serum level of estrogen is between about 35pg/ml and 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein a contraceptive, preferably an oral contraceptive, is administered after a short induction of treatment with an LHRH antagonist.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the non-steroidal anti-rheumatic agent is administered after a short induction of treatment with an LHRH antagonist.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the analgesic is administered after a short induction of treatment with an LHRH antagonist.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein an androgen other than a 17-alpha-alkyl substituted testosterone is administered after a short induction treatment with an LHRH antagonist.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein after short-term induction of treatment with an LHRH antagonist one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone or any combination thereof is administered in combination or separately.
According to a further aspect of the invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered starting at the early to mid follicular phase, preferably on days 1 to 3 of the cycle.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered in a weekly dose of 3 to 10 mg/week during a period of 4 to 12 weeks of short induction treatment.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered at a daily dose of 0.25 to 0.5 mg/day during the short induction treatment period of 4 to 12 weeks.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered at a monthly dose of 12 to 40 mg/month during a period of 4 to 12 weeks of short induction treatment.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein the LHRH antagonist is administered for 4 to 12 weeks of induction treatment and this treatment is repeated 2 or 3 times a year.
According to a further aspect of the present invention there is provided a pharmaceutical composition as described above wherein one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone or any combination thereof are in the same or separate dosage forms.
According to another aspect of the present invention there is provided the use of an LH-RH antagonist for the manufacture of a medicament for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), wherein the LHRH antagonist is administered to a patient in need of such treatment in the form of short-term induction of treatment for about 4 to 12 weeks, and then administration of the LHRH antagonist is discontinued.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered such that the estrogen is present at a serum level of between about 35pg/ml and about 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above in which a contraceptive, preferably an oral contraceptive, is administered after short-term induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the administration of the non-steroidal anti-rheumatic agent follows a short induction of treatment with the LHRH antagonist.
According to a further aspect of the invention there is provided the use of an LH-RH antagonist as described above in which the analgesic is administered after a short induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein an androgen other than a 17-alpha-alkyl substituted testosterone is administered after short-term induction treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above, wherein after short-term induction of treatment with the LHRH antagonist, one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone or any combination thereof are administered in combination or separately.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered starting at the early to mid follicular phase, preferably on days 1 to 3 of the cycle.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered in a weekly dose of 3 to 10 mg/week during a period of 4 to 12 weeks of short induction treatment.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered at a daily dose of 0.25 to 0.5 mg/day during a period of short induction treatment of 4 to 12 weeks.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered at a monthly dose of 12 to 40 mg/month during a period of 4 to 12 weeks of short induction treatment.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above wherein the LHRH antagonist is administered for 4 to 12 weeks of induction treatment and the treatment is repeated 2 or 3 times a year.
According to another aspect of the present invention there is provided the use of a LH-RH antagonist and one or more active agents selected from a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof for the manufacture of a medicament for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), wherein the LHRH antagonist is administered to a patient in need of such treatment for about 4 to 12 weeks in the form of short-term induction therapy, then administration of the LHRH antagonist is discontinued and one or more active agents selected from a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof is administered to the patient together or separately.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents in which the LHRH antagonist is administered such that the serum level of estrogen is between about 35pg/ml and about 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein a contraceptive, preferably an oral contraceptive, is administered after a short induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein the non-steroidal anti-rheumatic agent is administered after a short induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein the analgesic is administered after a short induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein an androgen other than a 17-alpha-alkyl substituted testosterone is administered after a short induction of treatment with the LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above in combination with one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof, or administered separately after a short induction of treatment with an LHRH antagonist.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is administered starting at the early to mid follicular phase, preferably on days 1 to 3 of the cycle.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
According to a further aspect of the present invention there is provided the use of a LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is administered at a weekly dose of 3 to 10 mg/week during a period of short induction treatment of 4 to 12 weeks.
According to a further aspect of the present invention there is provided the use of a LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is administered at a daily dose of 0.25 to 0.5 mg/day during a short induction treatment period of 4 to 12 weeks.
According to a further aspect of the present invention there is provided the use of a LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is administered at a monthly dose of 12 to 40 mg/month during a short induction treatment period of 4 to 12 weeks.
According to a further aspect of the present invention there is provided the use of an LH-RH antagonist as described above and one or more active agents wherein the LHRH antagonist is administered for a short induction treatment of 4 to 12 weeks and this treatment is repeated 2 or 3 times a year.

Claims (53)

1. In a method of treating extrauterine proliferation of endometrial tissue, chronic pelvic pain, and/or Fallopian Tube Obstruction (FTO), the improvement consisting of: in the form of short-term induction therapy, the LHRH antagonist is administered to a patient in need of such treatment for about 4 to 12 weeks, and then administration of the LHRH antagonist is discontinued.
2. The method according to claim 1, wherein the LHRH antagonist is administered to a serum concentration level of estrogen of between about 35pg/ml to about 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
3. The method of claim 1, wherein a contraceptive, preferably an oral contraceptive, is administered after short-term induction of treatment with the LHRH antagonist.
4. The method according to claim 1, wherein the short-term induction of treatment with the LHRH antagonist is followed by administration of a non-steroidal anti-rheumatic agent.
5. The method of claim 1 wherein the short-term induction treatment with the LHRH antagonist is followed by administration of an analgesic.
6. The method of claim 1 wherein the treatment with the LHRH antagonist for short induction is followed by administration of an androgen other than a 17-alpha-alkyl substituted testosterone.
7. The method of claim 1, wherein after short-term induction of treatment with the LHRH antagonist, one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than 17-alpha-alkyl substituted testosterone or any combination thereof are administered in combination or separately.
8. The method of claim 1, wherein the LHRH antagonist is administered beginning at the early to mid follicular phase, preferably on days 1 to 3 of the cycle.
9. The method of claim 1, wherein the LHRH antagonist is selected from the group consisting of cetrorelix, teverelix, ganirelix, antide, abarelix, and D-63153.
10. The method of claim 1, wherein the LHRH antagonist is administered at a weekly dose of about 3 to 10 mg/week during a period of about 4 to 12 weeks of short-term induction therapy.
11. The method of claim 1 wherein the LHRH antagonist is administered at a daily dose of about 0.25 to 0.5 mg/day during a period of about 4 to 12 weeks of short-term induction treatment.
12. The method of claim 1, wherein the LHRH antagonist is administered at a monthly dose of 12 to 40 mg/month during a period of about 4 to 12 weeks of short-term induction treatment.
13. The method of claim 1 wherein the LHRH antagonist is administered for short-term induction treatment for about 4 to 12 weeks, and this treatment is repeated 2 or 3 times a year.
14. A pharmaceutical composition for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), comprising an LHRH antagonist and optionally one or more components selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17-alpha-alkyl substituted testosterone or any combination thereof, and optionally pharmaceutically acceptable excipients, whereby, the LH-RH antagonist is administered to a patient in need thereof during a short induction treatment period of about 4 to 12 weeks, administration of the LH-RH antagonist is then discontinued and the patient is optionally administered, together or separately, one or more ingredients selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than 17-alpha-alkyl substituted testosterone, or any combination thereof.
15. The pharmaceutical composition of claim 14 wherein the LHRH antagonist is administered to a serum level of estrogen concentration of between about 35pg/ml to about 80pg/ml, preferably about 45-75pg/ml, and particularly preferably about 50-75 pg/ml.
16. Pharmaceutical composition according to claim 14 or 15, wherein a contraceptive, preferably an oral contraceptive, is administered after a short induction treatment with an LHRH antagonist.
17. A pharmaceutical composition as claimed in any one of claims 14 to 16 wherein the non-steroidal anti-rheumatic agent is administered after a short induction of treatment with an LHRH antagonist.
18. A pharmaceutical composition as claimed in any one of claims 14 to 17 wherein the analgesic is administered after short-term induction treatment with an LHRH antagonist.
19. A pharmaceutical composition as claimed in any one of claims 14 to 18 wherein an androgen other than a 17- α -alkyl substituted testosterone is administered after short-term induction treatment with an LHRH antagonist.
20. Pharmaceutical composition according to any of claims 14 to 19, wherein after short-term induction of treatment with an LHRH antagonist, one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than a 17-alpha-alkyl substituted testosterone or any combination thereof are administered in combination or separately.
21. A pharmaceutical composition as claimed in any one of claims 14 to 20 wherein the LHRH antagonist is administered starting at the early to mid stages of the follicular phase, preferably on days 1 to 3 of the cycle.
22. A pharmaceutical composition as claimed in any one of claims 14 to 21 wherein the LHRH antagonist is selected from cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
23. The pharmaceutical composition of any one of claims 14 to 22 wherein the LHRH antagonist is administered at a weekly dose of about 3 to about 10 mg/week during a period of about 4 to 12 weeks of short-term induction treatment.
24. The pharmaceutical composition of any one of claims 14 to 23 wherein the LHRH antagonist is administered at a daily dose of about 0.25 to about 0.5 mg/day during the short-term induction treatment period of about 4 to 12 weeks.
25. The pharmaceutical composition as claimed in any of claims 14 to 24, wherein the LHRH antagonist is administered at a monthly dose of about 12 to 40 mg/month during a period of about 4 to 12 weeks of short-term induction treatment.
26. A pharmaceutical composition as claimed in any one of claims 14 to 25 wherein the LHRH antagonist is administered for the induction of treatment for about 4 to 12 weeks and this treatment is repeated 2 or 3 times a year.
27. Pharmaceutical composition according to any of claims 14 to 26, wherein one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than a 17-alpha-alkyl substituted testosterone or any combination thereof are in the same or in separate dosage forms.
Use of a LH-RH antagonist for the preparation of a medicament for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), whereby the LH-RH antagonist is administered to a patient in need of such treatment for about 4 to 12 weeks in the form of short-term induction therapy, and then administration of the LH-RH antagonist is discontinued.
29. The use of an LH-RH antagonist as claimed in claim 28 wherein the LHRH antagonist is administered to achieve a serum estrogen concentration level of between about 35pg/ml and about 80pg/ml, preferably of about 45-75pg/ml, particularly preferably of about 50-75 pg/ml.
30. Use of a LH-RH antagonist according to claim 28 or 29 wherein a contraceptive, preferably an oral contraceptive, is administered after a short induction treatment with the LHRH antagonist.
31. Use of a LH-RH antagonist as claimed in any one of claims 28 to 30 wherein the non-steroidal anti-rheumatic agent is administered after short-term induction treatment with the LHRH antagonist.
32. Use of a LH-RH antagonist as claimed in any one of claims 28 to 31 wherein the analgesic is administered after short-term induction treatment with the LHRH antagonist.
33. Use of a LH-RH antagonist as claimed in any one of claims 28 to 32 wherein an androgen other than a 17- α -alkyl substituted testosterone is administered after short-term induction treatment with the LHRH antagonist.
34. Use of a LH-RH antagonist as claimed in any one of claims 28 to 33 wherein after short-term induction treatment with the LHRH antagonist, one or more active agents selected from the group consisting of contraceptives, preferably oral contraceptives, non-steroidal anti-rheumatic agents, analgesics, androgens other than a 17-alpha-alkyl substituted testosterone or any combination thereof are administered in combination or separately.
35. Use of a LH-RH antagonist as claimed in any one of claims 28 to 34 wherein the LHRH antagonist is administered starting at the early to mid stage of the follicular phase, preferably on days 1 to 3 of the cycle.
36. Use of an LH-RH antagonist as claimed in any one of claims 28 to 35 wherein the LHRH antagonist is selected from cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
37. The use of a LH-RH antagonist as claimed in any one of claims 28 to 36 wherein the LHRH antagonist is administered at a weekly dose of about 3 to about 10 mg/week during a period of about 4 to 12 weeks of short-term induction treatment.
38. The use of a LH-RH antagonist as claimed in any one of claims 28 to 37 wherein the LHRH antagonist is administered at a daily dose of about 0.25 to about 0.5 mg/day during the week of short-term induction treatment of about 4 to 12.
39. The use of a LH-RH antagonist as claimed in any one of claims 28 to 38 wherein the LHRH antagonist is administered at a monthly dose of about 12 to about 40 mg/month during the short induction treatment period of about 4 to 12 weeks.
40. Use of an LH-RH antagonist as claimed in any one of claims 28 to 39 wherein the LHRH antagonist is administered for about 4 to 12 weeks of induction treatment and this treatment is repeated 2 or 3 times a year.
Use of a LH-RH antagonist and one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17- α -alkyl substituted testosterone or any combination thereof for the manufacture of a medicament for the treatment of extrauterine proliferation of endometrial tissue, chronic pelvic pain and/or Fallopian Tube Obstruction (FTO), whereby the LHRH antagonist is administered to a patient in need of such treatment for about 4 to 12 weeks in the form of short-term induction therapy, followed by discontinuation of the administration of the LHRH antagonist and the patient is administered together or separately one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17- α -alkyl substituted testosterone or any combination thereof.
42. The use of a LH-RH antagonist and one or more active agents as claimed in claim 41, wherein the LHRH antagonist is administered to achieve a serum level of estrogen concentration of between about 35pg/ml and about 80pg/ml, preferably about 45-75pg/ml, particularly preferably about 50-75 pg/ml.
43. Use of a LH-RH antagonist and one or more active agents as claimed in claim 41 or 42 wherein a contraceptive, preferably an oral contraceptive, is administered after a short induction treatment with the LHRH antagonist.
44. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 43 wherein the non-steroidal anti-rheumatic agent is administered after a short induction of treatment with the LHRH antagonist.
45. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 44 wherein the analgesic agent is administered after a short induction of treatment with the LHRH antagonist.
46. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 45 wherein an androgen other than a 17- α -alkyl substituted testosterone is administered after a short induction treatment with the LHRH antagonist.
47. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 46 wherein after short-term induction treatment with the LHRH antagonist, one or more active agents selected from the group consisting of a contraceptive, preferably an oral contraceptive, a non-steroidal anti-rheumatic agent, an analgesic, an androgen other than a 17- α -alkyl substituted testosterone, or any combination thereof, are administered in combination or separately.
48. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 47 wherein the LHRH antagonist is administered starting at the early to mid stage of the follicular phase, preferably on days 1 to 3 of the cycle.
49. Use of an LH-RH antagonist as claimed in any one of claims 41 to 48 and one or more active agents wherein the LHRH antagonist is selected from cetrorelix, teverelix, ganirelix, antide, abarelix and D-63153.
50. The use of a LH-RH antagonist as claimed in any one of claims 41 to 49 and one or more active agents in which the LHRH antagonist is administered at a weekly dose of about 3 to 10 mg/week during a period of about 4 to 12 weeks of short induction treatment.
51. Use of an LHRH antagonist and one or more active agents as claimed in any one of claims 41 to 50, wherein the LHRH antagonist is administered at a daily dose of about 0.25 to 0.5 mg/day during a period of about 4 to 12 weeks of short-term induction treatment.
52. The use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 51 wherein the LHRH antagonist is administered at a monthly dose of about 12 to 40 mg/month during the short induction treatment period of about 4 to 12 weeks.
53. Use of a LH-RH antagonist and one or more active agents as claimed in any one of claims 41 to 52 wherein the LHRH antagonist is administered for the induction of therapy for about 4 to 12 weeks and the therapy is repeated 2 or 3 times a year.
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