CA2348160A1 - Use of antifungal agents for treating scleroses - Google Patents

Abstract

The invention concerns the use of active antifungal agents on fungi of the Candida genus, and as the case may be of the Rodhotorula genus, for preparing medicines for preventing or treating tissue scleroses, and other derived pathologies, in humans and animals, related to the presence in the human or animal organism of fungi derived from those mentioned above.

Description

USE OF ANTIFUNGALS IN THE TREATMENT OF SCLEROSES
The present invention relates to the use of antifungals active on the fungi of the genus Candida, and if appropriate on those of the genus Rodhotorula, for the preparation of medicines intended for the prevention or treatment of sclerosis tissue, and other derived pathologies, in humans or animals, related to the presence I
in (human or animal organism of fungi derived from those mentioned above above.
This invention stems from the discovery by the inventor of the fact that a antifungal active on Candida, known under the common name international (INN) Nystatin, helps absorb sclerosis of body tissues, when he is used, on the one hand at a dosage significantly lower than its dosage usual in the context the treatment of candidiasis, and, on the other hand, for a period of treatment a lot longer than the usual duration; candidiasis treatment.
This highlight is the result of many years of observations effects Nystatin. in vivo for long periods of treatment performed by (Inventor on himself.
In his autobiographical drunk published in Bulgaria on April 27, 1998 ("Chronicle of a Dance with thEr Devil ", by R.oumen Antonov, Pygmalion Press ISBN954-8336-39-1), the inventor shares the tests carried out on himself, and a few others volunteers, with a drug supposedly active against Candida albicans, without however designating this drug.
Having found that this drug, which in reality was Nystatin, had a effect of absorption of tissue necrosis or sclerosis originating from old scars, (Inventor hypothesized that these tissue sclerosis could result of development of Candida albicans in regions of (organism or accumulate dead cells and tissue debris.
This is how the Invent ~ zr looked for the presence of Candida albicans in of in vitro atheroma plaques. The e-xperience consists of incising a plaque atheroma and treat with a local liquid antifungal active against Candida albicans. We then notice WO 00/24403

2 PCT / FR99 / 0261'i reproducibly the in vitro decomposition of the atheroma plaque after addition of the antifungal.
In addition, the cultivation of these atheroma plaques makes it possible to observe a Y-shaped structure which, although relatively atypical, could suggest the presence of Candida albicans at (inside this atheroma plaque.
However, this simple observation alone did not allow us to conclude with certainty on the presence or absence of Candida albicans in plaques of atheroma. A
such confirmation required the implementation of experiments complementary.
Recent experiments of cultures on Sabouraud medium and colorings specific, in particular by fluorescence, of the microorganisms present in the plaques of atheroma, enabled the Inventor to conclude unambiguously on the presence of a fungus related to fungi of the genus Candida in plates atheroma, and other sclerotic tissues, although having filaments with dimensions never described so far for fungi of the genus Candida. Moreover, the inventor has thus could highlight that the aforementioned fungus was sometimes accompanied of a fungus of the genus Rodhotorula, the latter being itself for the first time described by the Inventor in filamentary form.
Furthermore, the in vivo studies carried out for a long time by the inventor, him have allowed to determine the antifungal dosages necessary for the prevention or treatment of pathologies, in particular various sclerosis, related to development of these fungi in the body.
The subject of the invention is a mushroom derived, in particular by mutation, from a fungus of the genus Candida, such as Candida lipolitica, or .larowia lipolitica, or derivative other germs or fungi, including other species of fungi lipolytics, said fungus being capable of developing in the perfect sexual phase under form filamentous in the human or animal organism, especially in the system vascular, the various organs, as well as in the skin.
The aforementioned mushroom is also characterized in that it is capable, after have been taken from a host, especially in atherosclerotic plaques human develop in vitro in a nutrient medium, such as Sabouraud medium, under made of filamentous colonies of whitish color, and of a substrate mycelium presenting filaments clearly visible in the nutrient medium.

WO 00/24403

3 PCT / FR99 / 02617 It can also be in the form of yeast colonies whitish fatty in relation to the nutrient medium, and corresponding to the fungus imperfect in asexual phase.
The fungus derived from the genus Candida mentioned above according to the invention is more charred in that it includes filaments whose diameter varies between about 4 to about 8 ~, and can reach up to more than 30 ~, in the middle nutritious in vitro, or in the body :.
The aforementioned mushroom of the invention is also characterized in that let it be ~
develops in an anaerobic environment, in vivo or in vitro.
The invention also relates to a fungus as defined above, deposited to the National Collection of Culture of Microorganisms (CNCM) of the Institute Pastor in Pans under number T-2336 on October 15, 1999.
The above mentioned mushrooms, and more particularly those derived from kind Candida as defined above according to (invention, are more characterized in that they can develop in the human or animal organism, in association or not with a fungus of the genus RodhotorN, ~ la, or a derivative of the latter, in particular in presence of Rodhotorula rubra or Rodhotorula glutinis or other subspecies of Rodhotorula, this fungus of the genus Rodhotorula possibly in filamentous form corresponding to a sexual form of these mushrooms in perfect phase, and this, like this has already been mentioned above, especially in vessels blood (such as veins, capillaries, arteries, arterioles, coronaries, etc.), or other tissues humans the the above mentioned mushrooms which can be extracted from this organism.
The invention also relates to the use of antifungals active on the Candida fungi, especially on Candida albicans, Candida lipolitica, or Jarowia lipolitica, and, if appropriate, on fungi of the genus Rodhotorula, such as Rodhotorula rubra or Rodhotorula glutinis, for the preparation of a medicament intended for prevention or treatment of pathologies linked to the presence in the human organism or animal of an aforementioned fungus, and more particularly of a derived mushroom of the genus Candida as defined above, in particular of a fungus derived from Candida lipolitica, or other germ, presenting the atypical filamentous structure mentioned above, the if necessary in association with a aforementioned fungus of the genus Rodhotorula, and / or in association with yeasts of the Candida lipolitica type.

WO OOI24403 PCT / FR99 / 026 t T

4 The invention more particularly relates to the use of antifungals such as defined above and below, for the preparation of a medicament intended for prevention or to the treatment of sclerosis or tissue necrosis, or pathologies from these sclerosis or necrosis, and being linked to the presence in the human organism or animal of mushrooms as described above, and more particularly of a mushroom derived from Candida genus as defined above, Ie if necessary in association with a mushroom mentioned above from the genus Rodhotorula.
The subject of the invention is more particularly the use mentioned above antifungals as described above, for the preparation of a medicine for prevention or treatment of pathologies linked to the development of sclerosis or necrosis in the body, namely a medicine intended to prevent or absorb them sceriosis or necrosis resulting from the deposition and accumulation of debris cell phones in tissues, as well as their maintenance in the form of clumps by fungi such as described above, and more particularly by fungi related to those of kind Candida as defined above, if necessary in combination with a mushroom mentioned above of the genus Rodhotorula, develop in these structures sclerotia or necrotic.
The invention also relates to (use of antifungals as defined above and below, for the preparation of a medicament intended for the prevention or Treatment of fathosclerosis linked to the presence in the body's blood vessels human or animal, fungi as described above, and more particularly of a fungus derived from the genus Candida as defined above, where appropriate in association with a above-mentioned fungus of the genus Rodhotorula, as well as different pathologies associated with the aforementioned atherosclerosis, such as infarction myocardium, phlebitis, and cerebrovascular thrombosis.
The invention also relates to the use of antifungals such as defined above above and below, for the preparation of a medicament intended for the prevention or treatment of sclerosis or necrosis of the skin, such as eczema, psoriasis, the erythema, ichthyosis, linked to the presence in the human or animal organism, of mushrooms as described above, and more particularly of a mushroom derived from genus Candida as defined above, if appropriate in combination with a mushroom mentioned above of the genus Rodhotorula, or of a drug intended for the detersion of necrotic scars and wounds and the elimination of sphaceles especially in cases ulcers (eg jarr: ~ bes) of venous origin; bedsores, traumatic wounds, chronic, ulcerated or dull, superficial and deep burns, necrosis skin of traumatic origin, within which is located the mushrooms mentioned above.
The invention also relates to the use of antifungals as defined above and below, powr the preparation of a drug intended for the prevention or Treatment of sclerosis or necrosis of the joints, especially in cases of osteoarthritis, related to the ' presence in the human or animal organism of fungi as described above on it, and more particularly from a fungus derived from the genus Candida as defined above, the if necessary in association with a aforementioned fungus of the genus Rodhotorula.
The invention also relates to the use of antifungals such as defined above above and below: rës, for the preparation of a medicament intended for the prevention or treatment of pulmonary diseases of sclerotic origins, and more particularly from asthma or spasmodic cough, linked to the presence in the human body or animal of mushrooms as described :. above, and more particularly of a derived mushroom of the genus Candida as defined above, where appropriate in association with a the above-mentioned fungus of the genus Rodhotorula.
By active antifungals s ~ .u- fungi of the genus Candida, and on those of the kind Rodhotorula, we mean notaxnrnent any compound active on any species of Candida genus and Rodhotorula, in particular any compound active on Candida Albicans, Candida lipolitica, or Jarowia lipc ~ litica, and any compound active on Rodhotorula rubra, or on any species or subspecies derived, in particular by mutation, from the above-mentioned fungi.
Among the antifungal agents likely to be used in the context of present invention we can cite - Flucyi: osine (INN), - antifungal contact antibiotics of the polyene family, - antifungals from the imidazole group, such as . the; Miconazole (DCI), . the; Ketoconazole (DCI), . the; Fluconazole (INN) (bistriazole antifungal}.

WO 00/24403 6 PC'T / FR99 / 0261 The subject of the invention is more particularly the use mentioned above polyene family of antifungal contact antibiotics, and more particularly those extracted from cultures of bacteria of the genus Streptomyces, such as . Amphotericin B (INN) extracted from culture of Streptomyces nodosus, . Nystatin (INN) extract from the culture of Streptomyces noursei, or any derivative of these antifungals, such as those obtainable by synthesis chemical.
By way of illustration, the polyenes capable of being used in the frame of the present invention are as follows - the following tetraenes of formula 1 . nystatin of formula la ... ~ :: ~ _ - r:; = v,. r: _: -: v- '. - ::::
_ _p _-._: Oy ::; O_H: ~ -: fold ._._. . ~: _ ~ _ -. .- _ '._ ~ = .: r' ~~ ~ .._ ~ .'_ ~: ..: W '~ yj.: .. ~. _'._ ~ i '. ::::'.
_- ~ .. 'y _'., ~ ':.;.:. .... ' ~ -i; ~; ~: ~ _:. - -f_. - -: .- - ~~ - ~ ~~~~ ~~ ~. ~ 1 = r, -: ~ i '~. ~ _ Ai. ~' _ 1 ~. l ; '.; v ~ ~ lv .. ~! '- y. _:,. -:. . -. _. ::. . ; . ' r '._ -';,'.' _. ~ -: _. ~ :: :: w -_ ':: "ï -_-_: ._ ~ - _.: -. - _ ::.:. ~ = - ~ y - - .--:. . ' .. ~. ;. . : ~ - _ _. - ..
-: v ..._ ..:.
. pimarycin of formula lb in which R = CH3 and farenomycin in which R = CHZ CH2-CHZ-CH3 :. . ... . r ...: ..., - .-. . :. ~ .... ~ COoEf -.
- -. . . . . .. - :. -; ..:. ~.
~ ..: ._-_: ._ .: ~ :: _ ~ _ .. ~:.: .._ .- _ .. :: ..... ~ _. . . _: ....
-; --..--. .: ~:.:>
. _ -.;. : ~ _-.._ -. _. - _- .. - '. ..:.
:: - _ .- _. -. ::,:, ..-. , WO 00/24403 ~ PCT / FR99 / 02617 . the rimocide of formula 1 c 8._ '_ _-- -. - :. ..: ..:.
- - NOT _.;
S -_ kt _ .oki _ ~ ... ~,. . _.
- ~ '-. .:. H '. . _: '-'' -. ~ _ -. - - 014 Nli ~
-: -.- -tetrine A of formula 1 d in which R = H, and tetrine B in which R = OH
'c ~
_ ..._..... ~: ..... .._: '.
- Pentaenes of the following formulas 2 . the philipine of formula 2a in which R = H, and the pentamycin in which R = OH
-..'- :: .'_ 'y ::. ~~ y, y: ~~ wyy, ~~: .. ~ pti ~~ ~ °:' ~ r ~ v ~ :: _.: .- :
. - ~ -.:; s: N ~.
:.: ~ :: -;,; ~ ': = :: ::' :. '~'~:; y. ' : _.,; ..; _ ~ :: ~ ... ~: ~ :: '_ ~:.:': ':: .'._'._ :: ~
~ r% = ': = ~ ï ~ ..'- :. ~ - '= ~ ~ ~ = ~:, - ..
: '_. . ~ '_ '.,. ::. _. . . . ~ ";' . _ . : ~ f! .. i._:. . ~~: ~: 'â.
;.; ', ~ .'1:.:,:: V' ~.: -._ ...:; . =: ~~, ': -i .._ .: r'i .; . :: y s. ;: ',: ::.. ::
._ '~:
~ i 'oi. -_ ~. . . - ~. -., r .- -:; y- - ... . ; -. . . _ .. ~ ..:.
. =: - - ~ :: -: .-. :::: ..: ~: ~ - v. ~ y.-_: =., .- -_._: -.:.; ~,: _ i WO 00/24403 g PCT / FR99 / 0261'1 . mycotitzin A of formula 2b in which R = H, and mycotitzin B of formula 2b in which R = CH3 . feirotitzine A of formula Zc in which R = CH3, and feirotitzine B of formula 2c in which R = H
... ... v r ~ .. ~ s -. . v /. ~ / v _. .
_. ~ -. : ~ - OIf. NNi the compound of formula 2d below '' . . , ~,. cR.

- hexa ~; nes of formulas. Next 3 . la de; rmostatine A dE: formula 3 in which R = CH3, and dermostatin B
of formula 3 in which R = C: H2-CH3 . _ _. . : ..., '..
_. t ~ ~ 14 ~ Ofl .v O! 1 r OH O (.t vv .v ~
_.
~ r ~.-_. ~. ~ '~ ~~''~, '3 ~ _, a. __ _. . ~.; ... . .. ... ... _ ..
..... -. _, - the following formula 4 heptaenes . famphotericin B of formula 4a w. '~. ~ ~ w ;. . : ~ ~ j ~;. ~.: ._ ~ ~. ~,: '-: _ Oç, ~. ~: ~ _pR .Y_ ~. ~.:. ~ y ~ ....: ~~ .. ..
.COaK .. ..
~ _ 'v. ~: ç ~, _ w _. . . ~ ~ .. y. ....: tï _.:, -.-: '. . 'pH.N::. ::. _ . f:. . . . y: -,. ~. '..
... ...:,. . . _. . ,. . . ~. :. "c ~, f . the candidine of formula 4b ~.
. _. ~ .._. _. ' i: ~ ..::.: .. ~.: '_' ~: ~. _. .
. .: ~. . ~ ~ ,,. ~ v! # ~ .. ~. . , ~. '~ ~.' . -. . _. Yes. ~. _ ~.
r_o .. _: _ ~ ...: .. r. J ..: _ .. '~: ~ ._. . .: (~ ~ ~
.. ~ _ ~ y ~:. -. . _. . . . 'ât ~ rr; ~
, ~. . s, yr ... ~. ~. . . v / ~~ Y ~ ._ '. .
. ~ .. ... _ ~, ',. \. .

WO 00/24403 10 PCT / FR99 / 0261'7 Advantageously, the antifungal used in the context of the present invention is here Nystatin.
Advantageously, the doses of antifungals used in the context of the present invention are about 2 to about 100 times including about 5 to about 50 times, lower than the usual doses of these same antifungals (i.e.
doses about 10 tablets of 500,000 IU per day for 10 days) in part of treatment of candidiasis including buccopharyngeal, intestinal or vaginal.
In addition, the duration of treatment is much longer, in particular at least I
about 5 times longer, in the case of the present invention, than in the case of treatment of the aforementioned candidiasis, and more particularly at least less about 2 months, especially at least around 6 months.
By way of illustration, the dosages used in the case of use of antifungals, and more particularly Nystatin, as part of the present invention are as follows - less than approximately 100,000 units per day in adults, especially in people between the ages of about 20 and 30 to 40, or - between approximately 25,000 and approximately 50,000 units per day in people of less about 20 years old, and in children, - between approximately 25,000 and approximately 125,000 units per week, advantageously about 25,000 units per week, in people over 40, for a period unlimited processing.
The dosages indicated above are given for one or more doses daily for the duration of treatment, or preferably for one or more multiple takes per day spaced at intervals of about 3 to about 7 days during the duration of treatment.
At the dosages indicated above, the duration of treatment is approximately minus 6 months for children and people under the age of about 20, up to or many years in people over 20 years of age.
It can be noted that after such processing periods, the system immune becomes able to take over from the development of these sclerosis or necrosis due to the development of fungi as described above, and more particularly of c, ~ aforementioned ampoules derived from the genus Candida, by a process immunization, for a period including approximately 3 years and about 5 years.
Treatment with the above-mentioned antifungals may then stop.
In the event that this immunization disappears, treatment with the help of aforementioned antifungals can then resume, preferably with dosages about two times lower than those indicated above, and for one duration approximately twice as short.
The dosages and durations cThe treatment indicated above allow to decrease by significantly the amounts of mushrooms as described above, ~
and more i ~
particularly the above-mentioned fungi derived from the genus Candida, as well that the if necessary, those of the genus Rodlaotorula, in the organism.
The inventio: also has for object, the aforementioned use antifungals such as described above, at dosages to stop growth said fungi in the body. In this case, the dosage used in the context of (use of antifungals, especially Nystatin, is advantageously about 25.00 () units per week (in one or more doses), at people from over 40 years, for an unlimited period of treatment.
The inventio: na also has for obj and the methods of treatment of pathologies above, by administration to patients likely to be treated, of the above-mentioned antifungals, in particular at the doses indicated above, and during the above-mentioned durations.
Advantageously, the abovementioned antifungal agents are used in the context of the present invention, for the preparation of medicaments capable of being administered by orally, especially in the form of tablets or oral suspensions, or by way injectable.
The invention will be further illustrated with the aid of the detailed description which follows from highlighting of fungi as defined above in biposias original human.
1 Patients This research was used for biopsies of vessels performed at (opportunity caz ~ dio-vascular operations performed on 69 patients, coming from two hospitals different.

The patients are distributed as follows: 50 men and 19 women, aged between 32 and 81 years old.
The materials collected during biopsies are ~ 137 in number, distributed according to their gender between: aorta 35; saphenous vein 30; carotid artery 17; artery breast 39; artery pulmonary, radial artery, etc. 6.
4 patients underwent 4 biopsies, 19 patients 3 biopsies, 13 patients 2 biopsies and 33 patients only one biopsy.
2. Methodology The biological materials were collected in the best conditions possible guaranteed sterility by hospitals during surgical operations. In course of operation, biopsies were placed in sterile containers and transported immediately at laboratory. In the laboratory, while the most sterile conditions strict were respected and the air controlled, the biological materials were cut into smaller 15 pieces for the rest of the work to be done and especially the preparation blades for direct observation, seeding in nutritious medium and conservation frozen for further research.
For the different biological materials, a maximum number of slices has been sought to increase the number of seeded slices. A control of the air was carried out by the sedimentation method on a solid nutrient medium in the field of work and during the whole period of work.
2.a. Prepared biological materials for direct observation under the microscope smear The smears were prepared as follows: a small piece of material biological was placed between two slides. Let dry and then fix the blades in using heat. From each biopsy we prepare a smear colored Gram -Modification of B ~ zuc: staining with crystal violet and carbon nitrate, lugol;
discoloration with acetone alcohol and obtaining the contrast with safranine.
The smear as well colored is observed under an inlrnersion microscope under objective x 100. Another smear is prepared for observation under fluorescence.

WO 00/24403 13 PCT / FR99 / 026t7 2.b. Seeding Microbiological seeding is done on a solid nutritive medium of Sabouraud, while seeking to obtain maximum contact of the material organic with the nutrient medium. For this, we cut the solid medium and inoculate the material organic in the cut obtained.
The nutrient medium contains g of Peptone Difco g of Difco Glucose 15 g Agar Difc: o 10 distilled water up to 1000 ml.
The medium is sterilized for 10 minutes at 121 ° C.
After seeding, the Petri dishes are rolled up with textile plaster; in order to reduce the risk of contamination during culture time.
The culture of the material is done at 28 ° C for 30 days by performing controls 15 daily without removing the sticking plaster from the Petri dishes.
2.c. Renic ~ ua ~ e of the pure strains obtained When we spot a growth of the plate towards the middle, we proceed, by respecting the sterility conditions mentioned above, when transplanting the strain obtained and again prepare a Gram stained smear to observe the strain at 20 microscope.
2.d. Identification To identify the fungal strains obtained, we use PAPI 32C from Bio Mérieux, which is used for yeast, as well as methods observations macroscopic and microscopic used for (morphological identification ~ others types of mycelium.
Out of 137 biopsies, 535 materials were cut and seeded primarily on the solid nutrient medium.

WO 00124403 14 PCT / FR99 / 026 i 7 ~
3. Results 3.a. Microscope results Out of 137 biopsies, 115 smears were taken for direct observation during of primary cutting of the organic pieces for sowing. We observed then under the microscope yeasts and / or filaments on 87% of the smears.
3.b. Isolated fungal strains In a large part of the biological materials sown and in variable periods of time, we observe shoots of fungal strains including the major part is a whitish, filamentous fungal strain with mycelium substrate with clearly visible filaments in the nutrient medium. These filaments come out directly from the biological material while very visibly making shapes concentric.
The time necessary for the clear appearance of a fungal colony is between the 4th and the 20th day after (primary seeding, with two points highlights Ie 6'm 'and the 13 ~ m' day. From September 21 to October 6, out of 50 patients, 21 have had biopsies with positive results (development of the strain) or 42%. It is interesting to note that the percentage of development of the strain is 75% for the patients who had 4 biopsies, 70% for those who had 3 biopsies and that percentage drops to 29-26% for those who have had 2 and 1 biopsies. By biopsy, the percentage of positive results is 28%.
The second type of fungal strains found according to its rate of presence in biological materials is Rhodotorula (Rubra, Glutinis).
He pushes directly from the biological material while entering the environment.
The identification of this strain was carried out by API 32C and it turned out that this is the Rhodotorula Rubra and of Rhodotorula Glutinis. Rhodotorula cases are distributed equal between patients from both hospitals. The Rhodotorula grows faster, between 3 and 7 days to from seeding. In most cases, it grows from the biopsy of a patient, where later will also grow the whitish filamentous strain, and represents 12 patients.
The third fungal strain according to its rate of presence in the biopsies turned out to be Candida Lipolitica (on 2 patients). In all the case she was isolated next to the whitish filamentous fungal strain.

~ ', WO 00/24403 PCT / FR99 / 02617 '15 During the research time, out of 3 of the 535 sowings carried out, seen growing strains of a different kind which, depending on where they had grown in petri dishes, were found to be contaminants because they had no direct relationship with the biological material.
In none of the Petri dishes with a nutrient medium and air control, we have not could find yeast or contaminants.

Claims (13)

16 1. Fungus derived, in particular by mutation, from a fungus of the genus candida, such as Candida lipolitica, or Jarowia lipolitica, said fungus being able to develop into the perfect sexual phase in filamentous form in the organism human or animal, especially in the vascular system, the various organs, as well as that in the skin. 2. Mushroom according to claim 1, characterized in that it comprises filaments whose diameter varies between approximately 4 to approximately 8µ, and can reach up to more of 30 µ in a nutrient medium in vitro or in the body. 3. Mushroom according to claim 1 or 2, characterized in that it is develops in anaerobic environment. 4. Mushroom according to one of claims 1 to 3, deposited in the Collection National Culture of Microorganisms (CNCM) of the Institut Pasteur in Paris under the number I-2336 on October 15, 1999. 5. Mushroom according to one of claims 1 to 4, characterized in that it can be develop in the human or animal body, in association with a fungus genus Rodhotorula, or with a derivative of the latter, in particular in the presence of Rodhotorula rubra or Rodhotorula glutinis. 6. Use of active antifungals on fungi of the genus Candida, and, the case appropriate on mushrooms of the genus Rodhotorula, for the preparation of a medication intended for the prevention or treatment of pathologies linked to the presence in the body human or animal of a fungus defined in one of claims 1 to 5, the case appropriate in association with a fungus of the genus Rodhotorula. 7. Use of antifungals according to claim 6, for the preparation of one medicinal product intended for the prevention or treatment of sclerosis or necrosis tissue, or pathologies resulting from these sclerosis or necrosis, and being linked to the presence in (human or animal organism of a fungus defined in one of the claims 1 to 5, where appropriate in association with a fungus of the genus Rodhotorula. 8. Use of antifungals according to claim 6 or 7, for the preparation of a medicinal product intended for the prevention or treatment of:
- atherosclerosis linked to the presence in the blood vessels of (organization human or animal, of a fungus defined in one of claims 1 to 5, the case appropriate in association with a fungus of the genus Rodhotorula, as well as different pathologies associated with the aforementioned atherosclerosis, such as infarction myocardium, phlebitis, and cerebral vascular thrombosis, - sclerosis or necrosis of the skin, such as eczema, psoriasis, erythema, ichthyosis, linked to the presence in the human or animal body of a mushroom defined in one of claims 1 to 5, where appropriate in combination with a fungus genus Rodhotorula, or a drug intended for the cleansing of scars and necrotic wounds and elimination of sphaceles, especially in cases original ulcers venous, bedsores, traumatic, chronic, ulcerated or sluggish wounds, burns superficial and deep, cutaneous necroses of traumatic origin, within which locates the fungus defined in one of claims 1 to 5, where applicable in association with a mushroom of the genus Rodhotorula, - sclerosis or necrosis of the joints, especially in cases osteoarthritis, related to the presence in the human or animal body of a fungus defined in one of claims 1 to 5, where appropriate in combination with a fungus of gender Rodhotorula, - pulmonary pathologies of sclerotic origin, and more particularly of asthma or spasmodic coughs, linked to the presence in the human organism or animal of a fungus defined in one of claims 1 to 5, where appropriate in association with a fungus of the genus Rodhotorula. 9. Use according to one of claims 6 to 8, of selected antifungals from following:
- Flucytosine (INN), - contact antifungal antibiotics from the polyene family, - antifungals from the imidazole group, such as . Miconazole (INN), . Ketoconazole (INN), . Fluconazole (INN) (bistriazole antifungal). 10. Use according to one of claims 6 to 8, of antibiotics antifungals contact of the polyene family, and more particularly those extracted from crops of bacteria of the genus Streptomyces, such as:
. Amphotericin B (INN) culture extract of Streptomyces nodosus, . Nystatin (INN) culture extract of Streptomyces noursei. 11. Use according to one of claims 6 to 8, of nystatin. 12. Use according to one of claims 6 to 11, antifungals, and more particularly Nystatin, at the following dosages:
- less than approximately 100,000 units per day in adults, especially in people between about 20 years old and about 30 to 40 years old, or - between about 25,000 and about 125,000 units per day in people less around 20 years old, and in children, or - between approximately 25,000 and approximately 125,000 units per week, advantageously about 25,000 units per week, in people over 40, for a period unlimited treatment. 13. Use according to claim 12, at the rate of one or more doses daily for the duration of the treatment, or, preferably, at the rate of a or many taken per day spaced at intervals of about 3 to about 7 days for the duration of the treatment, the duration of the treatment being approximately at least 6 months for the children and the people under about 20 years of age, up to one or more years in people over 20 years old.