EP1207902A2

EP1207902A2 - USE OF GROWTH HORMONE (hGH) FOR THE TREATMENT OF SEXUAL FUNCTIONAL DISTURBANCES

Info

Publication number: EP1207902A2
Application number: EP00949187A
Authority: EP
Inventors: Armin Johannes Becker; Christian Georg Stief; Stefan Ückert; Jonas UDO
Original assignee: Pharmacia AB; Pfizer Health AB
Current assignee: BECKER, ARMIN JOHANNES; Jonas Udo; STIEF, CHRISTIAN GEORG; UECKERT, STEFAN
Priority date: 1999-06-17
Filing date: 2000-06-15
Publication date: 2002-05-29
Also published as: WO2000078328A3; WO2000078328A2; JP2003502379A; CA2377339A1; AU6263500A; AU781842B2; NZ516223A

Abstract

The invention relates to the use of the human growth hormone (hGH, GH) either on its own or in combination with active substances which result in GH stimulation, have an effect which is analogous to GH or which promote the release of IGF-I in the production of medicaments which are used to treat sexual functional disturbances in both sexes. The invention also relates to a method for treating the above-mentioned dysfunctions.

Description

Use of growth hormone (hGH) for sexual therapy

Malfunctions

The invention relates to the use of human growth hormone (hGH, GH) for the manufacture of medicaments for the treatment of sexual dysfunctions of both sexes and methods for their treatment.

Sexual dysfunctions include e.g. lack or loss of libido, orgasmic disorders, insufficient lubrication and erectile dysfunction (ED). The aetiologies on which sexual dysfunctions are based, as far as they are at all clear, usually have a variety of causes. In addition to these mixed etiologies, vascular (arterial, venous), psychogenic, neurogenic, hormonal, drug-induced and cavernous sexual dysfunctions are distinguished.

Taking into account the underlying etiology (s), as far as possible, causal therapy for sexual dysfunction is sought. So far, however, this has only been possible in the most recent cases (e.g. through psychotherapy, hormone treatment, switching from medication), so that the majority of the therapies used remain unspecific.

In contrast to the therapy of female sexual dysfunctions, ED therapy in men already offers a variety of treatments. These include oral, topical, intracavernous, intraurethral, or combinations of pharmaceuticals, which, however, are not causal therapy, but are aimed at direct or indirect relaxation (relaxation) of the smooth cavernous muscles and the penile arteries. In connection with the resulting increase in blood flow, there is a penile erection. Furthermore, the vacuum pump, the arterial shunt procedures, venous blocking operations and penile prosthesis implantations are also used. Until the introduction of Sildenafil (Viagra®), mainly vasoactive substances to be administered intracavernously were used therapeutically. At the moment sildenafil is used as so-called "first line therapy", with the exclusion of existing contraindications. This too

CONFIRMATION COPY oral phosphodiesterase 5 inhibitor (PDE5), however, is not based on a causal therapy approach. Inhibition of PDE5 is said to inhibit the hydrolysis (breakdown) of cyclic guanosine monophosphate (cGMP) an intracellular messenger (second messenger), so that there is an increase in the relaxation of smooth erectile tissue muscles. This should also apply to women

Mechanism of action to improve lubrication, but this has not been confirmed in recent medical studies.

The object of the invention was therefore to provide the possibility of a new therapy for sexual dysfunction in men and women.

Surprisingly, it has now been found that growth hormone (hGH) plays an essential role in sexual arousal, since an enormous unexpected increase in this hormone was found at the beginning of sexual arousal.

The invention therefore relates to the use of hGH for the production of medicaments for the treatment of sexual functional disorders in men and women, such as, for example, a lack or loss of libido, orgasmic disorders, inadequate lubrication and erectile dysfunction, and the therapy of the functional disorders mentioned.

Another object of the invention is the use of hGH for the therapy of these functional disorders in a synergistic combination with active ingredients which lead to GH stimulation, have a GH-analogous effect or promote IGF-I release.

The scientific results described below are underlined by illustrations, which show the following.

Figure 1 shows the mean values and standard deviations of the

Growth hormone (hGH) concentrations (ng / ml) in the cavernous and peripheral blood samples during the 4 different erection phases (flaccidity, tumescence, rigidity and detumescence) in 35 healthy volunteers. Figure 2 shows the mean values and standard deviations of the growth hormone (hGH) concentrations (ng / ml) in the cavernous and peripheral blood samples during the 3 different erection phases (flaccidity, tumescence, and detumescence) in 36 patients with erectile dysfunction. Rigidity was not reached due to the illness. The

Axes were deliberately chosen as in Figure 1 to clearly identify the difference (p <0.05).

Figure 3 shows the mean values and standard deviations of the dose-dependent decrease in tissue tension (relaxation in%) of 12 human corpus cavernosum strips after application of recombinant hGH.

Figure 4 shows the mean and standard deviations of the dose-dependent increase in cyclic guanosine monophosphate (cGMP) from 3 human corpus cavernosum strips after incubation with recombinant hGH or nitroprusside sodium (SNP). Incubations were only carried out with SNP from a concentration of 0.01 nmol. For this reason, the value at 0.0001 nmol is missing for SNP.

In order to better understand the physiology of naturally induced erection and the pathophysiology of erectile dysfunction, a new examination method was developed. Here, the body's own human neurotransmitters, neuromodulators and hormones are detected, for which a

Connection with the erection or sexual function seems conceivable. The aim of this new examination method is to improve diagnostics and therapy (use of the body's own substances and thus causal therapy) in patients with sexual dysfunction.

Blood samples were taken from the corpus cavernosum (cavernous) and the cubital vein (peripheral) in parallel in 35 healthy volunteers during flaccidity, tumescence, rigidity and detumescence. Sexual stimulation was audiovisual and tactile (Figure 1). The procedure in 36 patients with ED was identical, with the exception of the lack of blood sampling during rigidity (this penile erection phase cannot be achieved in patients with ED) (Figure 2). The hGH concentrations were determined using an immunoradiometric assay (IRMA). With this study, which was carried out for the first time, several new insights could be gained.

1. The highest increase in hGH concentration was seen during tumescence, ie at the time of greatest sexual excitement.

2. In a direct comparison, the peripheral and cavernous hGH concentrations showed no significant differences in all penile erection phases.

Peripheral blood sampling is therefore sufficient.

3. In the comparison of the healthy volunteers with the patients, there were significant differences in the hGH concentrations, in particular a significantly reduced increase in the hGH concentration during the tumescence.

For the first time, these data show the surprising causal relationship between the hGH formed by the pituitary gland and sexual arousal and the resulting penile erection. The reduced expression of hGH under sexual stimulation in patients is further evidence of the importance of this hormone, the deficiency of which was associated with sexual dysfunction and especially erectile dysfunction in this study.

Through additional in vitro investigations with human corpus cavernosum (CC) tissue, important information for possible physiological connections between hGH and penile erection could be obtained in addition to the in vivo results described.

1. In organ bath tests (in vitro method for measuring the relaxing properties of substances) with human CC, dose-dependent relaxation after application of hGH could be measured (Figure 3). 2. In incubation experiments (in vitro method for measuring the content of cyclic nucleotides, here cGMP, after incubation with various substances) with human CC, higher cGMP concentrations were found depending on the dose after application of hGH than after incubation with nitroprusside sodium (SNP), a classic NO donor (Figure 4).

Based on our human results, it can be assumed that hGH, as a centrally formed hormone, plays a crucial role in sexual function (sexual arousal) and especially in penile erection. Furthermore, it has been shown that the peripheral reaction mediated by hGH induces an increase in cGMP in the CC, with which the relaxation of the CC is physiologically associated with the resulting erection. Due to the anatomical similarities in the structure of the penis and clitoris and the physiological agreement regarding sexual arousal (e.g. congestion of the genital organs through neurotransmitter-mediated relaxation of smooth muscles), this reaction described for hGH in men must apply to both genders, since hGH is a pituitary hormone occurring in both sexes, which must show the same effectiveness in women and men.

The effect of hGH is known so far that it is not focused on a specific tissue, but rather increases the activity and metabolism (anabolic) in both women and men in different tissues. The growth hormone stimulates, for example, body growth (substitution in the case of short stature due to hGH deficiency) and protein metabolism (possible indication for cachexia, severe burn injuries, and possible abuse as an anabolic steroid). Under the influence of hGH, insulin like growth factor I (IGF-I) is mainly formed in the liver, but also in other tissues. An important mediating role in the action induced by hGH is attributed to this polypeptide (IGF-I) (Merimee, TJ and Grant, MB: Growth hormone and its disorders. In: Principles and Practice of Endocrinology and Metabolism. Edited by Becker, KL, Philadelphia , JB Lippincott Company, pp. 125-134, 1990). The latest findings in humans have shown that substitution of recombinantly produced hGH (r-hGH) in patients with hGH deficiency led to a systemic increase in NO (nitrogen oxide) and cGMP (Böger, RH et al.: Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. J Clin Invest 98: 2706-2713, 1996). This NO-cGMP pathway is also assigned a very important positive meaning in the development of penile erection (Burnett, AL et al .: Nitric oxide: a Physiologie mediator of penile erection. Science, 257: 905, 1993). Also new knowledge from animal experiments in rats could show that there is an increase in NOS when hGH is substituted

Nerves (nitrogen oxide synthase) (generate NO) in the CC and dorsal penile nerves came after weeks before neurogenic damage was initiated (Jung, GW et al .: Growth hormone enhances regeneration of nitric oxide synthase-containing penile nerves after cavernous nerve neurotomy in rats. J Urol, 160: 1899-1904, 1998). The patent W098 / 42361 (Human erectile dysfunction and methods of treatment) is derived from these results and describes the indication of hGH therapy for the prevention and treatment of neurogenic erectile dysfunction of various causes (condition after extensive pelvic surgery or pelvic trauma, diabetes, alcoholism and age ).

For the first time, our results in humans show a positive causal relationship between sexual arousal, the increase in hGH and the penile erection. The reduced (often completely absent) increase in hGH in patients with ED underlines the importance of this hormone. The in vitro data suggest that the NO-cGMP pathway is activated by hGH and thus relaxes the CC, from which the penile erection results.

For the therapy according to the invention in all patients (of both sexes) with sexual dysfunctions, a peripheral blood sample is first taken to determine the basal hGH concentration, regardless of the underlying etiology (s). In the same session, then takes place under sexual stimulation (audiovisual, tactile) another blood sample with detection of the stimulated hGH concentration. If there is insufficient or no response to sexual stimulation (e.g. lubrication, penile erection) and there is insufficient increase in the hGH concentration, continuous, closely controlled therapy with hGH should be carried out for a longer period (e.g. 2-6 months).

Pharmaceutical preparations suitable for therapy are solid or liquid administration forms for oral administration, such as tablets, capsules or emulsions, parenteral administration forms for injection or for non-invasive administration, or transdermal topical systems such as plasters,

Ointments, gels, lotions or transdermal films. The amount administered for a successful therapy is 0.01 to 500 mg per dose unit, preferably between 0, 1 and 100 mg.

An improvement in the success of the therapy can be achieved by combination drugs containing, in addition to hGH in a synergistic combination, active ingredients which lead to GH stimulation, have a GH-analogous effect or promote IGF-I release.

However, these active ingredients do not necessarily have to be combined in one pharmaceutical, but can also be administered in separate suitable galenical preparations next to one another or separately according to a therapeutic regimen.

These active ingredients, administered alone, can already lead to the desired therapeutic success. It is known to the person skilled in the art how the suitable dosage, or which combination or which active ingredient can be determined for the best possible therapy, for example according to the determination and examination methods mentioned.

Furthermore, combinations of several of the classes of active substances mentioned can of course also be used for use or therapy according to the invention. The person skilled in the art is familiar with the suitable active substances mentioned as possible combinations, which lead to GH stimulation. Examples include arginine, alpha 1 and alpha 2 agonists such as clonidine, norepinephrine or salbutamol, glucagon, pyridostigmine, galanin, GH-releasing hormone, NPY (neuropeptide Y) and dopamine agonists such as apomorphine, quinpirole or cabergoline.

Suitable active substances which have a GH-analogous effect are, for example, GHRP (Growth Hormone Releasing Hexapeptide, Hexarelin), GH Releasing Peptide 1, 2, 6 and non-peptide-agonists of growth hormone releasing peptides such as MK 0677, EP 51389 (2-methylalanyl-2- methyl-D-tryptophyl-2-methyl -) - D-tryptophanamide), L 692429 (3-amino-3-methyl-N - [(3R) -2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1 H-tetrazol-5-yl) [1, 1'-biphenyl] -4-yl] methyl] -1 H-1-benzazepin-3-yl] butanamide), or L 692585 (3 - [[(2R) -2-Hydroxypropyl] amino] -3-methyl-N - [(3R) -2,3,4,5-tetrahydro-2-oxo-1 - [[2 '- (1 H-tetrazol-5-yl) [1, 1 '-biphenyl] -4-yl] methyl] -1 H-1 - benzazepin-3-yl] -butanamide).

Suitable active ingredients that promote IGF-I release include cannabinoids such as. B. HU-210 (3- (1, 1-dimethylheptyl) -6a, 7, 10, 10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b, d] pyran-9-methanol) or serotonin receptor agonists such as 8-OH DPAT (8-hydroxy-2- (dipropylamino) tetralin), or SC 53116 (4-amino-5-chloro-N - [[(1 S, 7aS) - hexahydro-1 H-pyrrolizin-1-yl ] methyl] -2-methoxy-benzamide).

Claims

Claims:

1.Use of growth hormone for the production of drugs for the therapy of female and male sexual dysfunctions such as lack or loss of libido, orgasm disorders, insufficient lubrication, erectile dysfunction) for all etiology (s) not to be treated causally, with insufficient increase in the concentration of hGH during sexual stimulation and a hGH deficiency.

2. Use of growth hormone according to claim 1 in combination with active ingredients which lead to GH stimulation.

3. Use of growth hormone according to claim 1 in combination with active ingredients that have a GH analog effect.

4. Use of growth hormone according to claim 1 in combination with active ingredients which promote IGF-I release.

5. Use of active ingredients that lead to GH stimulation according to claim 1.

6. Use of active substances which have a GH-analogous effect according to claim 1.

7. Use of active ingredients which promote IGF-I release according to claim 1.

8. Use of growth hormone for the therapy of female and male sexual dysfunctions such as lack or loss of libido, orgasm disorders, insufficient lubrication, erectile dysfunction) for all etiology (s) that cannot be treated causally, with insufficient increase in the concentration of hGH during sexual stimulation and with hGH Defect.

9. Use of active ingredients that lead to GH stimulation according to claim 8.

10. Use of active ingredients that have a GH-analogous effect according to claim 8.

11. Use of active ingredients which promote IGF-I release according to claim 8.