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WO2006060873A1 - Procede de restauration de la fonction reproductrice - Google Patents

Procede de restauration de la fonction reproductrice Download PDF

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Publication number
WO2006060873A1
WO2006060873A1 PCT/AU2005/001866 AU2005001866W WO2006060873A1 WO 2006060873 A1 WO2006060873 A1 WO 2006060873A1 AU 2005001866 W AU2005001866 W AU 2005001866W WO 2006060873 A1 WO2006060873 A1 WO 2006060873A1
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Prior art keywords
agonist
subject
amino acid
msh
seq
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PCT/AU2005/001866
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English (en)
Inventor
Iain J Clarke
George Antonatos
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Prince Henry's Institute Of Medical Research
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Priority claimed from AU2004907026A external-priority patent/AU2004907026A0/en
Application filed by Prince Henry's Institute Of Medical Research filed Critical Prince Henry's Institute Of Medical Research
Publication of WO2006060873A1 publication Critical patent/WO2006060873A1/fr

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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • 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
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • 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

Definitions

  • the present invention relates generally to the field of endocrinology and, particularly, to methods of regulating the fertility of a subject. More particularly, the present invention relates to methods of enhancing or restoring reproductive function in a subject who is reproductively impaired.
  • Amenorrhea in women may be the result of excessive exercise, or may be due to other reasons such as psychological stress, prior use of oral contraceptives or anorexia nervosa (Marshall, 2001). It is well established that amenorrhea of extremely lean women is due to extremely low fat and hypothalamic dysfunction, and adipose tissue, once thought to be only an energy source, has now been recognised as having a significant role in the regulation of female reproduction. It is also well recognised that significant decreases in body weight can result in lower circulating levels of reproductive hormones, a condition known as hypogonadotrophic hypogonadism.
  • LH and FSH serum luteinising hormone and follicle stimulating hormone
  • LH is a glycoprotein produced in both men and women from the anterior pituitary gland in response to luteinising hormone-releasing hormone (LHRH or GnRH) released by the hypothalamus, which in women has an important role in fertility and, particularly, in the stimulation of ovulation.
  • LHRH hormone-releasing hormone
  • the secretion of GnRH from the hypothalamus is pulsatile and this causes pulsatile secretion of LH.
  • the secretion of FSH is also controlled by GnRH, but the pulsatile pattern of secretion of this hormone is not as clear as for LH, because it has a longer half -life in plasma and may be secreted in the absence of GnRH.
  • Control of the serum level of LH concentration in healthy menstruating women is subject to the complex ovulatory cycle and, more specifically, depends upon a sequence of hormonal events along the gonado-hypothalamic-pituitary axis. That is, control of the serum level of LH is affected by the levels of progesterone and oestradiol that vary across the ovulatory cycle. Rising FSH levels stimulate the production of ovarian follicles (which contain the eggs, or ova). One or more follicles burst at the time of ovulation to discharge ova into the fallopian tubes of the female reproductive tract. The ovulatory cycle is divided into different phases depending upon the secretion of GnRH, the gonadotropins and ovarian hormones.
  • the "luteal phase” is characterised by low levels of GnRH and gonadotropins and high levels of progesterone, secreted from the corpus luteum of the ovary. During the luteal phase, GnRH and LH are secreted at low frequency. The corpus luteum forms from the ovarian follicle after ovulation. When the corpus luteum regresses, progesterone levels fall and the "follicular phase” begins. This is a phase of the cycle dominated by rising levels of oestrogen, secreted by one or more growing ovarian follicles. The pulse frequency of GnRH and LH increases in the follicular phase.
  • hypothalamic amenorrhea is a condition in which ovulation and failure of the regular ovulatory cycle is due to reduction in the secretion of GnRH from the hypothalamus. This leads to the loss of production and secretion of the gonadotropins and loss of ovarian function.
  • Leptin is a 167 amino acid, fat-derived, hormone that is a product of the ob gene, which is believed to act as a satiety factor, limiting food intake. Leptin acts on the brain to signal metabolic function. Leptin levels in serum are proportional to the amount of white fat and therefore acts as a "barometer" of relative adiposity.
  • Leptin also acts on cells in the brain that regulate food intake and energy expenditure.
  • the control of homeostasis is a very complex process, involving various types of brain cells and systems and there is neuronal communication between the appetite regulating systems and the neuroendocrine systems.
  • the latter comprises the cells of the hypothalamus that regulate the endocrine system, by production and secretion of releasing factors specific for each system.
  • GnRH regulates the reproductive system by acting on the gonadotropes of the pituitary gland and thyrotropin releasing hormone (TRH) act on thyrotropes of the pituitary to regulate the thyroid axis etc.
  • TRH thyrotropin releasing hormone
  • leptin Whilst leptin provides a means of restoring reproductive function in women suffering from hypothalamic amenorrhea, due to low body weight, it is known that administration of leptin may have adverse effects. For example, as a large protein hormone, continued administration may lead to the production of antibodies. Further, leptin also has peripheral effects on a range of tissues/organs, such as the ovary, so effects of parenteral administration are not specifically related to the neuroendocrine control of reproduction. In addition, leptin is a relatively large polypeptide and is therefore expensive to produce in commercial quantities (eg by recombinant technology).
  • the present invention is based on the surprising finding that the administration of an agonist of a melanocortin receptor can restore or enhance reproductive function in animals of low body weight, particularly in such animals showing reduced gonadotropin secretion.
  • the present invention provides a method of restoring or enhancing reproductive function in a subject that is reproductively impaired, the method comprising administering to said subject an melanocortin-3 and/or melanocortin-4 receptor (ie MC3-R and/or MC4-R) agonist in an amount sufficient to restore or enhance reproductive function.
  • an melanocortin-3 and/or melanocortin-4 receptor ie MC3-R and/or MC4-R
  • the present invention provides the use of an MC3-R and/or MC4-R agonist in the preparation of a medicament for restoring or enhancing reproductive function in a subject that is reproductively impaired.
  • Figure 1 illustrates the experimental design for the Experiment described in Example 1.
  • Figure 2 shows the effect of the non-receptor specific melanocortin agonist, MTII, on the secretion of LH in OVX ewes of low body weight.
  • Figure 3 shows the LH secretory profile of OVX ewes of low body weight receiving either aCSF or MTII.
  • the present invention provides a method of restoring or enhancing the reproductive function in a subject that is reproductively impaired, the method comprising administering to said subject an MC3-R and/or MC4-R agonist to the subject in an amount sufficient to restore or enhance reproductive function.
  • the present invention is particularly suitable for women that are reproductively impaired, but is also suitable for reproductively impaired men.
  • men also secrete luteinising hormone (LH).
  • LH stimulates testosterone production in the Leydig cells in the testes of men, where spermatogenesis takes place, and testosterone is also necessary for libido and secondary sexual characteristics such as muscle bulk.
  • An increased serum LH level in men markedly increases intratesticular testosterone levels, which, in combination with an increased serum FSH level, enhances sperm production.
  • administration of an MC3-R and/or MC4-R agonist will result in an increase in testosterone production and subsequent restoration or enhancement of reproductive function.
  • the present invention may also be useful in restoring or enhancing reproductive function in male and female non-human animals.
  • the term "subject” also extends to non-human animals and particularly, non-human mammals such as companion animals (eg dogs, cats and the like) and livestock (eg horses, cows, sheep and the like).
  • Reproductively impaired subjects which can be treated with the present invention include infertile and sterile subjects.
  • Reproductively impaired women who can be treated with the present invention will typically suffer from a deficiency in the hormonal system that supports ovulation, conception and/or maintenance of pregnancy.
  • Reproductively impaired men who can be treated with the present invention will typically suffer from a deficiency in the hormonal system that renders the subject incapable of impregnating women.
  • the hormonal deficiency suffered by these male and female subjects will typically occur in the gonado- hypothalamic-pituitary axis resulting from dysfunction within the brain to reduce the secretion of GnRH.
  • subjects treated with the present invention will be reproductively impaired through chronic malnutrition, hypogonadotropic hypogonadism or excessive exercise, although the present invention generally has utility for any form of idiopathic hypothalamic hypogonadism.
  • the melanocortin receptors are members of the G-protein coupled receptor class, which display seven transmembrane regions as a hallmark, and interact with a group of peptides (ie "melanocortin peptides") all of which are derived from the processing of proopiomelanocortin (POMC) by the converting enzymes pro-convertase 1 and 2 as well as carboxypeptidase E.
  • These processed peptides include adrenocorticotrophic hormone (ACTH), alpha melanocyte-stimulating hormone ( ⁇ -MSH), ⁇ -MSH, ⁇ -MSH, ⁇ -lipotrophin and the opioid, ⁇ -endorphin.
  • ACTH adrenocorticotrophic hormone
  • ⁇ -MSH alpha melanocyte-stimulating hormone
  • ⁇ -MSH alpha melanocyte-stimulating hormone
  • ⁇ -MSH alpha melanocyte-stimulating hormone
  • ⁇ -MSH al
  • MCl-R has been found predominantly in skin, and when stimulated, it acts to regulate pigmentation and reduce a number of inflammatory processes (Schioth, 2001).
  • MC2-R is present in the adrenal gland and has a high affinity for ACTH and will not bind to other melanocortin peptides (Schioth, et al 1996).
  • ⁇ -MSH acts upon MC3-R and MC4-R which are both predominantly expressed within the central nervous system. They exist in various regions and nuclei of the brain. MC4-R, however, is found only in the central nervous system, and its distribution is varied and overlapping in areas including the cortex, brainstem, spinal cord, and hypothalamus.
  • both the MC3-R and MC4-R can be found in the medial pre-optic area, paraventricular nucleus, dorsal medial hypothalamus, ventral medial hypothalamus and the arcuate nucleus (Iqbal, et a ⁇ 2001).
  • MC5-R is expressed in peripheral tissue and while it has been linked to exocrine gland function, there is yet to be any function of it linked to metabolic homeostasis.
  • MC3-R and/or MC4-R agonist refers to any agent which is capable of interacting with and activating a melanocortin-3 and/or melanocortin-4 receptor.
  • the term therefore encompasses, inter alia, the natural melanocortin peptides which interact with either or both of these receptors (eg ⁇ -MSH) and agents which are analogues thereof.
  • the MC3-R/MC4-R agonist used in the present invention include those that may restore or enhance serum LH levels to within a range considered normal for a healthy subject.
  • the MC3-R/MC4-R agonist is an ⁇ -MSH, ⁇ -MSH or ⁇ -MSH analogue, and particularly an MC3-R/MC4-R agonist comprises the amino acid sequence:
  • MC3-R/MC4-R agonist is an cyclic ⁇ -MSH analogue. Even more preferably, the MC3-R/MC4-R agonist is the cyclic ⁇ -MSH analogue known as melanotan II (MTU) having the amino acid sequence:
  • a related peptide or peptide-mimetic showing at least 75%, and more preferably at least 85%, amino acid sequence identity.
  • Examples of such related peptides or peptide- mimetics are provided by US Patent No 6,613,874, WO01/00224, WO01/13112, WO03/006620 and WO02/064091 (the entire disclosures of which are to be regarded as incorporated herein by reference).
  • Particularly suitable related peptides and peptide- mimetics are those incorporating one or more conservative amino acid substitutions of the amino acid sequence shown as SEQ ID NO: 2.
  • the peptide of SEQ ID NO:2 has a terminal -OH at the carboxy terminus to provide:
  • the MC3-R/MC4-R agonist is administered in an amount sufficient to restore the level of luteinising hormone (LH) to within a normal reference range (see Table 1).
  • LH luteinising hormone
  • the normal range will typically vary depending upon whether the particular subject is pre-pubertal, menopausal, or whether the subject is in the follicular, mid-cycle or luteal phase of the menstrual cycle.
  • the normal range will typically vary depending upon whether or not the particular subject is pre-pubertal.
  • Table 1 shows normal reference ranges for serum LH
  • the MC3-R /MC4-R agonist may be administered by routes of administration conventionally used for the delivery of drugs including oral, intranasal, transdermal, subcutaneous, intradermal, intravenous, intramuscular, and intraperitoneal administration.
  • the MC3-R /MC4-R agonist may be administered in any suitable form including injectable formulations, tablets, suspensions, implants, solutions, emulsions, capsules, powders, syrups and water compositions.
  • the MC3-R /MC4-R agonist may also be administered with any pharmaceutically acceptable (eg a buffered aqueous carrier, preferably a saline or citrate buffered carrier, vehicle, adjuvant, additive or diluent).
  • the present invention therefore also provides the use of an MC3-R/MC4-R agonist in the preparation of a medicament for restoring or enhancing reproductive function in a subject that is reproductively impaired.
  • an MC3-R /MC4-R agonist administered in accordance with this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the type of MC3-R /MC4-R agonist to be administered, the route of administration, the state of being of the subject, and the severity of the reproductive impairment being treated.
  • the MC3-R/MC4-R agonist is administered at a dose of about 0.5 ⁇ g/kg of body weight to about 75 ⁇ g/kg of body weight.
  • a subject is administered multiple doses of a MC3- R/MC4-R agonist over a period of days or weeks.
  • Administration of the MC3-R/MC4-R agonist to the subject can also preferably be a controlled release delivery over a period of days or weeks.
  • the treatment may be continuous over a period of preferably about 1 to 2 weeks.
  • the MC3-R/MC4-R agonist is preferably formulated for controlled release of the agonist (eg a depot administration) or for sustained release of the agonist.
  • the MC3-R/MC4-R agonist is formulated in a long- acting form having a relatively long plasma half -life.
  • MC3-R/MC4-R agonist in small continuous doses is preferred.
  • the advantage of such a continuous treatment is that long term treatment of a reproductive impaired subject is possible and controlled continuous treatment reduces the incidence of side effects in the subject. Therefore, the MC3-R/MC4-R agonist may be formulated in an osmotic dosage form that can be delivered at a controlled and continuous rate over time.
  • Surgical procedures were all carried out under a general anaesthetic. Each ewe initially received an intravenous injection of Bothamal (7.0ml Pentothal; Pharm Tech Pty Ltd, West Pymble, Sydney, NSW, Australia) by needle puncture into the jugular vein in order to induce general anaesthesia. An endotracheal tube was then introduced in order to allow the animal to breathe freely without any obstruction to airflow and to allow inhalation of anaesthesia.
  • Bothamal 7.0ml Pentothal; Pharm Tech Pty Ltd, West Pymble, Sydney, NSW, Australia
  • the wool surrounding the surgical sites at the head and neck were clipped and cleaned using Betadine Surgical Scrub (7.5% w/v PVP- iodine surgical scrub, Apex Laboratories Pty Ltd., Somersby, NSW, Australia) and 70% ethanol solution (Yarraville Distillery, Yarraville, Vic, Australia). The animal was then covered in surgical drapes leaving only the surgical site exposed.
  • lateral ventricular cannula Following placement of lateral ventricular cannula, the surgical site was sprayed with an antibiotic, Terramycin (Pinkeye aerosol, oxytetracycline hydrochloride 2.0mg/g; Pfizer Animal Health, West Ryde, NSW, Australia).
  • Terramycin Pieris aerosol, oxytetracycline hydrochloride 2.0mg/g; Pfizer Animal Health, West Ryde, NSW, Australia.
  • Ovariectomies were performed at least 6 weeks prior to the commencement of the experiment under standard sterile conditions and general anaesthetic.
  • a midline abdominal incision was made next to the midline and blind dissection was used to part muscle and fat layers.
  • Surgery commenced with a midline incision made in the peritoneum.
  • the uterus was located and the ovarian blood vessels were clamped and ligated just below the ovary.
  • the ovary above the clamp was exteriorised and removed with the use of a scalpel.
  • the peritoneum and external skin layers were sutured. Bleeding was controlled with electro cauterisation.
  • a guide tube with obturator was connected to surgical jig in order to guide LV tubing in to the ventricle.
  • the silastic tubing was introduced in 18mm from dura and it was observed to see whether CSF would flow out.
  • the cannula guide tube was then carefully removed to leave LV line in position.
  • the drapes were then held back with the use of clips and 2ml of radio-opaque dye (Omniopaque 300mg/ml, Nycomed Australia, Pty, Ltd, Chatswood, NSW, Australia) was injected into the line and the lateral ventricle.
  • An X-Ray cassette was placed at the opposite lateral side of the ewes head than the X-Ray machine (Atomscope HF200) which was moved into position and a lateral X-ray was taken. Once the X-ray had developed, the exact positioning of the LV line was visualised and determined whether or not it needed further readjustment. A second X-Ray was then taken to confirm its position after the dye had cleared from the LV (5 minutes). Next small amounts of subcutaneous tissue were cut and glued using superglue over the top of the cannula. Small amounts of Gelfoam (Pharmacia & Upjohn, Kalamazoo, USA), a sterile absorbable gelatine sponge were also placed and glued at the site of the LV line and the bone.
  • a suture was used to stitch up the dura (wax coated Softsilk braided silk 30' 75cm Black coated), and again to stitch up the skin (wax coated Softsilk braided silk 18' 45cm black coated) with the use of artiomatic needle taking care not to remove or alter the position of the cannula.
  • a cannula (12G x 9cm, Dwellcath, Tuta Laboratories, Lane Cove, NSW, Australia) was inserted into the jugular vein and stitched to the skin using silk suture. The catheter was then flushed with heparinized sterile saline (100 units/ml) and closed with a three-way stopcock (Connecta, Becton Dickinson, Helsringborg, Sweden).
  • the polyethylene tubing line was fastened to the wool of the ewe with elastic bands and leucoplast tape in order to ensure that no loose tubing could tear off. Finally the tubing was connected to the LV line. This was achieved through removal of a 20 gauge lcm blunt end already connected to the LV line, and replacing it with the 23 gauge stainless steel tubing from the polyethylene tubing line. The connection was then fastened with leucoplast tape.
  • the drug treatments were all diluted in artificial CSF (aCSF: 15OmM NaCl, 1.2mM, CaC12, ImM MgC12, 2.8mM KCL) to ensure solution availability throughout the infusion period.
  • aCSF artificial CSF
  • LH Luteinising Hormone
  • Day one of the assay consisted of adding 200 ⁇ l of assay buffer (0.5 % egg white in 0.02M PBS, pH 7.4) to each of the quality control, zero binding and sample tubes.
  • assay buffer 0.5 % egg white in 0.02M PBS, pH 7.4
  • Each ovine LH "standard tube” (NIH-SI8-0LH, with concentrations of 0.5, 1, 2, 3, 5, 10, 20, 50 ng/ml) received lOO ⁇ l of buffer and lOO ⁇ l of Hypophysectomised sheep plasma to make up a standard curve of samples.
  • lOO ⁇ l of the plasma sample was added to the sample tubes.
  • oLH antibody solution for addition to sample tubes, a lOO ⁇ l aliquot of oLH antibody (NIDDK-anti-oLH-I) was diluted to a concentration of 1:700 000 through the addition of 70ml of normal rabbit serum 1:2000, (1.89% EDTA in 0.02M PMS pH 7.4). 200 ⁇ l of this solution was then added to all tubes with the exception of the nonspecific binding and total count tubes. In order to correct the volume for the non-specific binding tubes, 200 ⁇ l of normal rabbit goat serum was added.
  • ovine LH (NIH-NIDDK, AFP8614B) was iodinated using idogen l,3,4,6-tetrachloro-3 ⁇ ,6 ⁇ -diphenylglcouril (Sigma StXouis, MO, USA) to label the purified oLH with 125 I (NEN Life Science Products, Boston, Massachusetts, USA) according to the protocol by Salacinski PR et al (1981).
  • This iodinated hormone was stored in a concentrated form at 4°C and diluted as tracer in buffer when needed
  • the tracer was prepared through the dilution of 5 ⁇ l of 125 I-OLH in 20ml of assay buffer to give an activity of approximately 15 000 counts per minute per lOO ⁇ l. lOO ⁇ l of tracer was added to each tube. Once addition of all appropriate reagents was complete, every tube was vortexed to ensure proper mixture of the reagents. The tubes were then covered with a layer of foil and incubated for 20-24 hours at 32°C. The second day of the assay (or 14 hours following incubation), involved the addition of 200 ⁇ l of secondary goat anti-rabbit antibody (Werribee GAR24/2, 24/1). This solution was made up to 200ml, with 0.02M PBS. This was added to all tubes except for the total counts tubes. AU tubes were then vortexed again and incubated for 20-24 hours at 32°C with foil covering all tubes.
  • the third day of the assay required all tubes except for the total count tubes to be centrifuged for 30 minutes at rate of 3000 rpm to allow for the separation of the bound and unbound hormone. Following this, the tubes were immediately placed on ice and the supernatant aspirated. Every tube was then counted for 2 minutes using a Gamma counter containing the Multicalc® operation (1470 Wizard; Wallac Oy, Finland). The data of counts detected by the counter was then computed to levels of LH in ng/ml with the use of an in-house RIA program by Lee, et al (1976).
  • Hormonal levels of LH were characterised by the pulse amplitude, the pulse frequency, the mean baseline concentration, the response of 1 st pulse and the mean concentration. These characterisations were based on previous secretory profile of LH described by Scott CJ et al (1992).
  • a pulse was defined as having occurred when the assay value of a given sample exceeded the assay value of the previous sample by at least three times the standard deviation (SD) of the previous sample.
  • the baseline concentration was the lowest hormone value preceding the consistent rise in sample concentration.
  • the pulse amplitude was calculated as the difference between the pulse peak and the baseline concentration and the inter-pulse interval was the average time (min) in minutes, between two successive peaks.
  • SPSS SPSS Inc., Chicago, Illinois.
  • the between-subjects factor was the type of treatment the ewe received and the within subjects factor was the time that the sampling took place, pre or post treatment.
  • the pulse frequency was testing using a non parametric chi squared test.
  • LH (ng/ml) secretory profile of a control ewe (C-736, #265) receiving aCSF and a treatment ewe (C-736, #363) receiving MTII is shown in Figure 3, both ewes are OVX ewes of low bodyweight.
  • the first three hours of blood sampling represent the pre-treatment period whereas the last three hours of blood sampling represent the post- treatment period.
  • Treatment with MTII showed a clear increase in LH in the post- treatment period.
  • Schioth, HB The physiological role of melanocortin receptors. Vitam. Horm. 63:195-232, 2001.

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Abstract

La présente invention concerne un procédé de restauration ou d’amélioration de la fonction reproductrice chez un sujet présentant des troubles de la reproduction. Ledit procédé consiste à administrer audit sujet un agoniste des récepteurs de la mélanocortine-3 (MC3-R) et/ou de la mélanocortine-4 (MC4-R) en quantité suffisante pour restaurer ou améliorer la fonction reproductrice.
PCT/AU2005/001866 2004-12-09 2005-12-09 Procede de restauration de la fonction reproductrice WO2006060873A1 (fr)

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AU2004907026 2004-12-09
AU2004907026A AU2004907026A0 (en) 2004-12-09 Method for restoring reproductive function

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Cited By (6)

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WO2009043504A2 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009043505A2 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US8487073B2 (en) 2008-06-09 2013-07-16 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of sexual dysfunction
US8492517B2 (en) 2009-11-23 2013-07-23 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
US8933194B2 (en) 2009-11-23 2015-01-13 Palatin Technologies, Inc. Melanocortin-1 receptor-specific linear peptides
US9040663B2 (en) 2009-06-08 2015-05-26 Astrazeneca Ab Melanocortin receptor-specific peptides

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WO2001000224A1 (fr) * 1999-06-29 2001-01-04 Palatin Technologies Inc. Compositions et methodes de traitement de dysfonctionnements sexuels
WO2002064091A2 (fr) * 2001-02-13 2002-08-22 Palatin Technologies, Inc. Metallopeptides de melanocortine pour le traitement de dysfonctions sexuelles
WO2003006620A2 (fr) * 2001-07-11 2003-01-23 Palatin Technologies, Inc. Peptides lineaires et cycliques specifiques du recepteur de melanocortine
US6613874B1 (en) * 1999-03-29 2003-09-02 The Procter & Gamble Company Melanocortin receptor ligands

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US5576290A (en) * 1993-04-05 1996-11-19 Competitive Technologies, Inc. Compositions and methods for the diagnosis and treatment of psychogenic erectile dysfunction
US6051555A (en) * 1993-04-05 2000-04-18 Hadley; Mac E. Stimulating sexual response in females
US6613874B1 (en) * 1999-03-29 2003-09-02 The Procter & Gamble Company Melanocortin receptor ligands
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US10017539B2 (en) 2009-11-23 2018-07-10 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic hexapeptides
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