BE1028115B1 - Composition for the treatment of cancer - Google Patents

Abstract

The invention relates to a composition comprising mesterolone, and optionally melatonin, for its use in the context of the prevention or prevention treatment of atrophy, adenoma and prostate cancer.

Description

Description Title of the invention: Composition for the treatment of cancers The invention relates to a composition for the treatment and prevention of cancers, in particular cancers of the prostate.

The prostate is a gland in the male reproductive system. Located just below the bladder, like a ring, it surrounds the urethra, the channel through which urine and semen exit the body. The role of the prostate is to produce prostatic fluid, one of the components of semen along with seminal fluid and sperm, to temporarily store semen before ejaculation, then to contract at the time of ejaculation, thus participating in expulsion. semen.

The prostate is made up of a collection of elements called lobules, made up of supporting tissue containing smooth muscle fibers, blood vessels, and nerve endings.

Among the various cancers occurring during the life of men, prostate cancer is the most common cancer. It is estimated that one in seven men will be diagnosed with it, most often in their 60s.

Most prostate cancers grow very slowly, and prostate cancer itself is not generally responsible for male mortality. Often, the tumor remains localized in the prostate and has limited health effects, sometimes causing urinary or erectile dysfunction. However, it may happen that certain cancers evolve and spread more rapidly.

Also, there is a need to provide means for treating and preventing the occurrence of prostate cancer.

Currently the main non-surgical treatments for prostate cancer are the use of analogs or antagonists of luteinostimulin-releasing hormone (LHRH), which block the production of testosterone by the testes.

However, these treatments have the effect of causing erectile dysfunction in patients, an overall drop in libido, but above all weight gain and loss of bone mass.

Another pathology of the prostate involves its atrophy due to age, or as part of the treatment of cancer. This atrophy is linked to a deficiency in dihydrotestosterone, a regulator that controls the growth of prostate structures. This condition is usually treated with testosterone, which unfortunately has major side effects that are well known in older people.

Also, there is a real need to provide effective treatments without side effects in the context of various pathologies of the prostate, atrophy 5 or cancer.

The aim of the invention is therefore to overcome these disadvantages of the prior art.

The invention therefore provides a composition comprising mesterolone, for its use in the context of the prevention or prevention treatment of pathologies of the prostate, in particular in the context of atrophy, adenoma and cancer. Prostate cancer.

The invention is based on the surprising finding made by the applicant according to which mesterolone improves the state of health of men, in particular elderly men and, on the one hand, prevents prostate atrophy, but also limits the occurrence of cancers. prostate cancer and treatment-related side effects.

The use of mesterolone, which is a mimetic of dihydrotestosterone, is classically contraindicated in cases of prostatic pathologies, as stipulated in the pharmaceutical leaflet accompanying mesterolone.

Contrary to the known contraindication from the prior art, the Applicant demonstrates here that mesterolone is beneficial in the context of prostatic pathologies.

Mesterolone, or 1α-methyl-4,5a-dihydrotestosterone; or alternatively 1α-methyl-Ba-androstan-17B-ol-3-one, is a synthetic steroid exhibiting anabolic and androgenic activities. Mesterolone has the following formula: [Chem 1]

Oh this

H The Applicant has come to the conclusion that the progressive decrease in androgenic hormones has a detrimental effect on the prostate. This decrease can be counteracted by the administration of mesterolone.

In humans, dihydrotestosterone (DHT) deficiency is the first step in anabolic hormone deficiency. This is because DHT is a final hormone of androgen anabolism, testosterone being a precursor of DHT, as dehydroepiandrosterone (DHEA) is a precursor of testosterone. Neither testosterone nor DHEA can replace dihydrotestosterone. Also, such substitution treatment cannot significantly counteract DHT deficiencies in the long term.

During aging, DHT is the last link in the androgen chain which is no longer or insufficiently produced, causing sexual problems in men.

This means that all androgen production begins to decrease, although non-sexual functions are, apparently in part, spared.

Mesterolone, derived from DHT, although known for a long time is neglected by the medical profession because it has only a weak anabolic power.

The age-related decrease in the amount of dihydrotestosterone also causes, simultaneously with atrophy of the prostate, an involution of the sexual organs thus causing impotence, ejaculation and libido disorders. At the physiological level, the deficit in dihydrotestosterone induces progressive fibrosis of the muscles of the prostate; smooth muscles become fibrous and unable to open during urination thus causing urinary disorders.

This is why the atrophy of the prostate is reversed, in particular as part of a preventive treatment, with mesterolone to prevent the progression of atrophy of the prostate muscle mass or to prevent a relapse after endoscopic surgery having removed the fibrous tissue. Properly proportioned administration of mesterolone to men who do not / no longer produce dihydrotestosterone prevents fibrous transformation of the prostate musculature and stabilizes sexual disturbances.

In the context of prostate adenoma, the Applicant has also demonstrated that mesterolone stabilizes or decreases prostatic volume.

Here again, the treatment and prevention of prostate adenoma with mesterolone is contrary to usual medical recommendations. Indeed, it is commonly established to use inhibitors of 5 alpha reductase to treat prostate adenomas, while these inhibitors have the effect of inhibiting the formation of dihydrotestosterone necessary for the proper functioning of prostatic structures.

On the other hand, these 5-alpha reductase inhibitors automatically cause an excess of estradiol production, which is responsible for the growth of the prostate adenoma. By inhibiting the formation of dihydrotestosterone, it promotes the accumulation of testosterone upstream in the androgen production chain. And by increasing the estradiol precursor testosterone, upstream we increase the production of estradiol responsible for the growth of the adenoma.

The administration of mesterolone decreases the production of testosterone and therefore the production of estradiol causing adenoma while maintaining

€ BE2020 / 5139 physiological androgenism by mesterolone, the actual role of which on the prostate glands remains to be clarified.

Prostate cancer generally refers to cancer of the prostate glands. This must be understood in view of the fibromuscular structure of this organ. There are benign or cancerous tumors of the muscles of the prostate.

All men are ultimately affected by abnormalities in prostate cells since the hormonal production of dihydrotestosterone gradually decreases with age. Pathological studies show that all men 90 and over have cancer cells in the prostate.

Individual variations in the production of dihydrotestosterone cause some men to develop cancer earlier than others. However, other concomitant age-related biochemical deficiencies also promote the development of cancer in general and prostate cancer in particular.

Although the role of dihydrotestosterone is not well understood in prostate cancer, it is notable that the suppression of dihydrotestosterone causes an increase in the activity of normal prostate cells, leading to tumor development.

Also, and in a manner contradictory to the studies carried out, and to the suppression of the production of testosterone in subjects suffering from prostate cancer, the Applicant has been able to observe that the administration of well-proportioned mesterolone to men presenting a production deficit of dihydrotestosterone prevents, or even limits, the multiplication of normal prostate cells in the absence of any known carcinogenic factor (nicotine, pollution, endocrine disruptors, papoptosis disruptors). The applicant's data show that the administration of mesterolone in men suffering from prostate cancer, with a level of prostate specific antigen (PSA) elevated at round 6, decreases the level of total PSA under treatment. .

Also, and surprisingly, the Applicant has been able to demonstrate a beneficial effect of mesterolone on pathologies of the prostate.

Advantageously, the invention relates to the above-mentioned composition, for its use as described above, where said adenoma and prostate cancer are hormone-dependent, in particular steroid-dependent.

The effects of mesterolone are particularly suitable for preventing and treating cancers emanating from prostate cells sensitive to DHT deficiency, and therefore steroid-dependent.

> BE2020 / 5139 Also, it is possible to see the emergence of prostate cancers from cells insensitive or not very sensitive to DHT, and therefore whose mesterolone replacement effect will not counteract.

More advantageously, the invention relates to the above-mentioned composition for its use as described above, said composition comprising from 10 to 50 mg of mesterolone.

In the invention, by “10 to 50 mg” is meant doses of 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg , 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 ma, 26 , 5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, 35 mg, 35.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg , 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg or 50 mg of mesterolone.

These doses of mesterolone are the most appropriate and are adapted according to the patient considered.

The pharmaceutical composition may be in the form of a cachet, a pill, a powder soluble in a liquid or intended to be suspended in a liquid, for example in the form of a syrup, a gel, an injectable solution, an impregnated composition allowing transdermal administration or through the mucous membranes. Those skilled in the art are able to determine the most appropriate galenic form to allow the administration of the desired dose.

In the invention, the above-mentioned dose is moreover advantageously administered daily. This means that the dose can be administered, in a single take, or in several intakes, for example twice a day (morning and evening for example) or even three times a day (morning, noon and evening for example) according to the recommendations of the doctor. Here again, those skilled in the art will know how to adapt the dosage regimen according to the individual to be treated, the objective being to administer the aforementioned dose.

In addition to the aforementioned mesterolone, the composition may comprise other substances whose function is to promote the effect of mesterolone without however having as such a specific preventive or therapeutic effect on pathologies of the prostate. Mention may be made, for example, of one or more additives such as those chosen from fillers, preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate or m-cresol, antioxidants, agents.

© BE2020 / 5139 stabilizers such as L-lysine hydrochloride, acidifying and basifying agents, opacifiers, etc.

The invention further relates to a composition comprising or consisting essentially of esteroin and melatonin.

Melatonin or N-acetyl-5-methoxytryptamine, is known to be the central hormone regulating chronobiological rhythms by being synthesized especially at night. Its chemical structure is as follows: [Chem 2] Mal

RS

WN NN OM 2 Melatonia regulates many hormonal secretions in humans and other mammals. This hormone is synthesized from a neurotransmitter, serotonin, which itself is derived from tryptophan. It is secreted by the pineal gland (in the brain) in response to the absence of light.

Like many other hormones, it seems that production decreases sharply as we age, and it varies depending on the individual.

Research has therefore shown that melatonin reduces tumor growth, cell proliferation and inhibits angiogenesis. For researchers, it has the potential of a therapeutic agent for breast cancer, especially since it does not appear to be toxic.

Given the anticancer properties of melatonin in cancer in general, and the significant decrease in its secretion by the body from the age of 50, the applicant proposes to provide a composition of the two hormones mesterolone and melatonin, making it possible to combine the effects of the two hormones, in particular concerning the pathologies of the prostate.

Advantageously, the invention relates to the aforementioned composition, comprising: - from 10 to 50 mg of mesterolone, and - from 5 to 10 mg of melatonin, in particular in combination with a pharmaceutically acceptable vehicle.

The Applicant proposes to combine melatonin at doses of 5 milligrams and 10 milligrams, with mesterolone for prevention, in particular in the context of the treatment and prevention of cancer, and in particular of prostate cancer. These doses are to be used taking into account the biology of androgens, PSA and ie BE2020 / 5139 urinary dosage of the metabolite of melatonin-6-sulfatoxymelatonin in urine 24 hours after intake.

In the invention, the term “from 5 to 10 mg of melatonin” is understood to mean doses of 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5, 6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg , 6.7 mg, 6.8 mg, 6.9 mg, 7 mg, 7.1 mg, 7.2 MG, 7.3 mg, 7.4 ma, 7.5 mg, 7.6 mg, 7 , 7 mg, 7.8 mg, 7.9 mg, 8 mg, 8.1 mg, 8.2 mg, 8.3 Mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 ma, 9 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 and 10 mg of melatonin.

By pharmaceutically acceptable vehicle is meant in particular an aqueous, sterile, preferably isotonic, solution, and in particular water, NaCl or a buffered saline composition, dextrose, glycerol, ethanol, or any other organic solvent or aqueous, or a combination thereof.

The definitions relating to the aforementioned dosage form apply here mutatis mutandis.

The invention further relates to the above-mentioned composition as a medicament, i.e. a medicament comprising 10 to 50 mg of mesterolone, and 5 to 10 mg of melatonin.

The invention also relates to the aforementioned composition, for its use in the context of the prevention or prevention treatment of pathologies of the prostate, and in particular atrophy, adenoma and prostate cancer.

In particular, the above-mentioned composition for its use as defined above is such that the adenoma and prostate cancer are hormone-dependent, in particular steroid-dependent.

The therapeutic composition is indicated for men from the age of 50 when the production of melatonin decreases considerably, just like that of testosterone. As the prevention of diseases of aging requires the daily intake of different hormones, the value of a hormonal composition comprising mesterolone and melatonin is evident in simplifying the daily intake of preventive treatment.

Examples About thirty patients are studied over an observation period which extends from 4 to 10 years. These patients presented spontaneously to the consultation without being recruited.

The observation principle is as follows: the time T1 is arbitrarily fixed for each patient at the year 2000; the time TO is for each patient fixed by the year of the start of the substitution with male hormones. I! This involves comparing the averaged and smoothed observation parameters for all 30 patients before (TO) and after (T1) substitution with androgens. A / Inclusion criteria: All the patients observed are still undergoing treatment. The average age is 5 over 50 (the consensus framework for andropause). All of these patients received strong androgens continuously for the duration of the observation. > A systematic digital rectal examination was performed on each patient before starting treatment, as well as an ultrasound check, in case of doubt. - The first total PSA measured for each of the patients was always less than 4ng / ml. Use of the same technique for measuring total PSA: “Hybritech method” ‘The biological tests were performed once a year for each of these patients. B / Reasons for the consultation: Out of the 30 patients observed: - 18 complained only of sexual disorders. Among them 11 presented at the outset a benign prostatic hypertrophy - Â complained only of prostate disorders - 5 complained of sexual and prostatic disorders: 3 consulted to prevent aging C / Observation period: | Number of patients || Duration of observation (year) |

PE | 18

B | 8 D / Choice of therapy: Of the 30 patients observed: 15 were treated with Andractim® (androstanolone) 15 were treated with Proviron® (mesterolone) none of the patients received Chibro-Proscar® ( finasteride) E / Observation parameters: For each patient the following parameters are recorded before and after substitution:

PSA the general genitourinary symptoms and prostatic volume. S-DHEA (DHEA sulfate) testosterone, DHT (didhydrotestosterone) are the biological parameters of androgen substitution monitoring. F / Significance of total PSA; Choice of total PSA as criterion of prostatic activity: Increases with the volume of the prostate; increases a lot in case of prostate cancer or prostatitis. - Good sensitivity and specificity between 2 and 4 ng / ml. - Good witness of the quality and "quantity" of the prostate.

A / Total PSA RESULTS Between TO and T1, there is an average reduction of 60% in total PSA; this reduction is obtained on average after two years of substitution, and then stabilizes. One can note a reduction of 50% of the standard deviation, that is to say a gathering of the values of the total PSA around the mean value. Mean total PSA at TO: 1.78 ng / m1 (+1.34) Mean total PSA at T1: 1.11 ng / m1 (+0.66) B / Symptoms Signs of sexual decline, as well as prostatic signs as a whole have been improved in almost 90% of cases. C / Volume Out of 30 patients treated, prostate volume stabilized for 21 of them, decreased for 6 of them and increased for 3 of them. D / Biological parameters of the observation: Average values of the parameters at TO: - DHEA: 1542 ng / ml {+ 830) - Testostrone: 5.2 ng / ml (+1.59) - Dihydrotestosterone: 0.55 ng / mi (+0.3) Average parameter values at T1: - DHEA: 1037 ng / ml (+ 538) - Testosterone: 2.64 ng / ml (+1.35) - Dihydrotestosterone: 2.93 ng / mi ( +2)

DISCUSSION A. The Choice of Total PSA as a Prostate Monitoring Method There is a statistical relationship between the fall in total PSA and the reduction in prostate volume. In the same way a relation exists between the symptomatology and the PSA

- 40 - BE2020 / 5139 total. This statistical relationship does not prevent classic monitoring by ultrasound and digital rectal examination.

The prostate volume is not always related to the total PSA (3 cases out of 30 in the present observation).

B. Non-statistical study: observation of a small number of patients over the medium and long term There are very few published studies concerning androgen replacement therapy in non-hypogonadic patients. Most of them concern weak androgens and do not exceed two years of substitution.

The difficulty in carrying out the observation and the low number of cases observed can be explained by the severity of the inclusion criteria.

CONCLUSIONS Treatment with mesterolone or androstanolone reduces total PSA on average over the long term, urinary symptoms and signs of sexual decline disappear, prostate volume is stabilized.

The study mixed 15 cases treated with mesterolone with 15 cases treated with dihydrotestosterone. The study was therefore clinical and limited, involving 11 cases of prostate adenoma. According to this study, it is not possible to separate, on the one hand, the action of mesterolone and on the other hand, the action of dihydrotestosterone itself. However, since mesterolone is metabolized to dihydrotestosterone, reduction of prostate adenoma or stabilization of prostate size by mesterolone is indicative of its action similar to DHT.

One explanation would be as follows: as the administration of mesterolone causes a decrease in testosterone in the blood secondary to a decrease in its production, the conversion of testosterone to estradiol decreases. The proliferative hormone estradiol, promotes the growth of the prostate glands. If there is less estradiol produced, there is less growth of the prostate glands. There is also a decrease in the level of PSA in all 30 cases studied [mean total PSA at TO: 1.78 ng / m1 (+1.34); Average total PSA at T1: 1.11 ng / m1 (+0.66)].

Claims (9)

Claims BE2020 / 5139 1. Composition consisting of mesterolone, for its use in the prevention of pathologies of the prostate, said pathologies of the prostate being atrophy, adenoma and cancer of the prostate. 2. Composition according to claim 1, wherein said adenoma and prostate cancer are hormone-dependent, in particular steroid-dependent. 3. A composition according to any one of claims 1 or 2, said composition comprising from 10 to 50 mg of mesterolone. 4. Composition consisting of mesterolone and melatonin. 5. Composition according to claim 4, consisting of: - from 10 to 50 mg of mesterolone, and - from 5 to 10 mg of melatonin. 6. A composition according to claim 4 or claim 5, in association with a pharmaceutically acceptable vehicle. 7. A composition according to any one of claims 4 to 6, as a medicament. 8. Composition according to any one of claims 4 to 7, for its use in the prevention of prostate pathologies, in particular atrophy, adenoma and prostate cancer. 9. The composition of claim 8, wherein said adenoma and prostate cancer are hormone-dependent, in particular steroid-dependent.