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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the use of antifungals active on fungi of the genus Candida, and if necessary on those of the genus Rodhotorula, for the preparation of medicaments intended for the prevention or treatment of tissue sclerosis, and other derived pathologies , in humans or animals, linked to the presence in the human or animal body of fungi derived from those mentioned above.
• This invention stems from the discovery by the inventor of the fact that an antifungal active on Candida, known under the international common name (INN) Nystatin, makes it possible to absorb sclerosis of the tissues of the organism, when it is used, on the one hand at a dosage significantly lower than its usual dosage in the context of the treatment of candidiasis, and, on the other hand, for a duration of treatment much longer than the usual duration of treatment of candidiasis.
• INN international common name
• the experiment consists of incising an atheroma plaque and treating it with a local liquid antifungal active against Candida albicans. We then see reproducibly the in vitro decomposition of the atheroma plaque after addition of the antifungal.
• the subject of the invention is a fungus derived, in particular by mutation, from a fungus of the genus Candida, such as Candida lipolitica, or Jarowia lipolitica, or derived from other germs or fungi, in particular other species of lipolytic fungi, said being able to develop in perfect sexual phase in filamentous form in the human or animal organism, in particular in the vascular system, the various organs, as well as in the skin.
• the above-mentioned fungus is also characterized in that it is capable, after having been taken from a host, in particular in plaques of human atheromas, to develop in vitro in a nutritive medium, such as Sabouraud medium, in the form of filamentous colonies of whitish color, and of a substrate mycelium having clearly visible filaments in the nutritive medium. It can also be in the form of whitish yeast colonies with a fatty appearance compared to the nutrient medium, and corresponding to the imperfect fungus in the asexual phase.
• a nutritive medium such as Sabouraud medium
• the fungus derived from the genus Candida mentioned above according to the invention is further characterized in that it comprises filaments whose diameter varies between approximately 4 to approximately 8 ⁇ , and can reach up to more than 30 ⁇ in nutritive medium m vitro , or in the body.
• the above-mentioned fungus of the invention is also characterized in that it develops in an anaerobic medium, in vivo or in vitro.
• the invention also relates to a fungus as defined above, deposited at the
• the above-mentioned fungi and more particularly those derived from the genus Candida as defined above according to the 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 Rodhotorula, or a derivative of the latter, in particular in the presence of Rodhotorula rubra or Rodhotorula glutinis or other subspecies of Rodhotorula, this fungus of the genus Rodhotorula being optionally in filamentous form corresponding to a sexual form of these fungi in perfect phase , and, as already mentioned above, more particularly in blood vessels (such as veins, capillaries, arteries, arterioles, coronaries, etc.), or other human tissues, the aforementioned fungi being extractable from of this organization.
• blood vessels such as veins, capillaries, arteries, arterioles, coronaries, etc.
• a subject of the invention is also the use of antifungal agents active on fungi of the genus Candida, in particular 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 the prevention or treatment of pathologies linked to the presence in the human or animal body of a mushroom mentioned above, and more particularly of a mushroom derived from the genus Candida as defined above, in particular of a fungus derived from Candida lipolitica, or other germ, having the above-mentioned atypical filamentous structure, where appropriate in association with a above-mentioned fungus of the genus Rodhotorula, and / or in association with yeasts of the Candida lipolitica type.
• a more particular subject of the invention is the use of antifungals as defined above and below, for the preparation of a medicament intended for the prevention or treatment of sclerosis or tissue necrosis, or of pathologies resulting from these scleroses or necroses, and being linked to the presence in the human or animal organism of fungi as described above, and more particularly of a fungus derived from the genus Candida as defined above, where appropriate in combination with an aforementioned fungus of the genus Rodhotorula.
• a more particular subject of the invention is the above-mentioned use of antifungal agents as described above, for the preparation of a medicament intended for the prevention or treatment of pathologies linked to the development of sclerosis or necrosis in the body, namely a medicament intended to prevent or reduce sclerosis or necrosis resulting from the deposition and accumulation of cellular debris in the tissues, as well as from their maintenance in the form of clumps by the fungi as described above , and more particularly by fungi related to those of the genus Candida as defined above, if necessary in association with a aforementioned fungus of the genus Rodhotorula, developing in these sclerotic or necrotic structures.
• the invention also relates to the use of antifungals as defined above and below, for the preparation of a medicament intended for the prevention or treatment of atherosclerosis linked to the presence in the blood vessels of the human or animal organism, fungi as described above, and more particularly a fungus derived from the genus Candida as defined above, where appropriate in combination with a aforementioned fungus of the genus Rodhotorula, as well as different pathologies associated with the aforementioned atherosclerosis, such as myocardial infarction, phlebitis, and cerebral vascular thrombosis.
• Another subject of the invention is the use of antifungals as defined 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, erythemas, ichthyoses, linked to the presence in the human or animal organism, of fungi as described above, and more particularly of a fungus derived from the genus Candida as defined above, the if necessary in combination with a aforementioned fungus of the genus Rodhotorula, or a drug intended for the detersion of necrotic scars and wounds and the elimination of sphaceles, especially in cases of ulcers (for example of the legs) of venous origin, bedsores, traumatic, chronic, ulcerated or dull wounds, superficial and deep burns, necrosis skin of traumatic origin, in which the aforementioned mushroom (s) is located.
• a medicament intended for the prevention or treatment of sclerosis or necrosis of the skin such as e
• the invention also relates to the use of antifungals as defined above and below, for the preparation of a medicament intended for the prevention or treatment of sclerosis or necrosis of the joints, in particular in the case of osteoarthritis , linked to the presence in the human or animal organism of fungi as described above, and more particularly of a fungus derived from the genus Candida as defined above, where appropriate in association with a aforementioned fungus of the genus Rodhotorula.
• the subject of the invention is also the use of antifungals as defined above and below, for the preparation of a medicament intended for the prevention or treatment of pulmonary pathologies of sclerotic origin, and more particularly of asthma or spasmodic cough, linked to the presence in the human or animal organism of fungi as described above, and more particularly of a fungus derived from the genus Candida as defined above, where appropriate in association with an aforementioned fungus of the genus Rodhotorula.
• antifungals active on fungi of the genus Candida and on those of the genus Rodhotorula, is understood in particular to mean any compound active on any species of the genus Candida and Rodhotorula, in particular any compound active on Candida Albicans, Candida lipolitica, or Jarowia lipolitica, and any compound active on Rodhotorula rubra, or on any species or subspecies derived, in particular by mutation, from the above-mentioned fungi.
• antifungal agents capable of being used in the context of the present invention, there may be mentioned:
• Fluconazole (bistriazole antifungal).
• a more particular subject of the invention is the above-mentioned use of antifungal contact antibiotics of the polyene family, and more particularly those extracted from cultures of bacteria of the genus Streptomyces, such as:
• Amphotericin B extracted from culture of Streptomyces nodosus
• Nystatin extracted from culture of Streptomyces noursei, or any derivative of these antifungals, such as those capable of being obtained by chemical synthesis.
• polyenes capable of being used in the context of the present invention are the following:
• the antifungal used in the context of the present invention is Nystatin.
• the doses of antifungals used within the framework of the present invention are approximately 2 to approximately 100 times, in particular approximately 5 to approximately 50 times, lower than the usual doses of these same antifungal agents (namely at the usual doses of approximately 10 500,000 IU tablets per day for 10 days) as part of the treatment of candidiasis, especially buccopharyngeal, intestinal or vaginal.
• the duration of treatment is much longer, in particular at least about 5 times longer, in the case of the present invention, than in the case of the treatment of the abovementioned candidiasis, and is more particularly at least about
• the dosages used in the case of the use of antifungals, and more particularly of Nystatin, in the context of the present invention are the following: - less than approximately 100,000 units per day in the adult, especially in people between the ages of about 20 and 30 to 40, or
• the dosages indicated above are given for one or more intakes daily during the duration of the treatment, or, preferably, for one or more intakes per day spaced apart by intervals of approximately 3 to approximately 7 days during the duration of the treatment .
• the duration of treatment is approximately at least 6 months for children and people under the age of about 20, up to one or more years in people over the age of 20.
• the immune system becomes able to take over against the development of these scleroses or necroses due to the development of fungi as described above, and more particularly of the aforementioned fungi derived from the genus Candida, through a process immunization, for a period of between approximately 3 years and approximately 5 years. Treatment with the above-mentioned antifungals may then stop.
• treatment with the abovementioned antifungal agents can then resume, preferably with dosages approximately two times lower than those indicated above, and for a period approximately twice as short.
• the dosages and durations of treatment indicated above make it possible to significantly reduce the amounts of fungi as described above, and more particularly of the aforementioned fungi derived from the genus Candida, as well as, if appropriate, those of the genus Rodhotorula, in the body.
• the invention also relates to the aforementioned use of antifungals as described above, in dosages which make it possible to stop the growth of said fungi in the body.
• the dosage used in the context of the use of antifungals, and more particularly of Nystatin is advantageously around 25,000 units per week (in one or more doses), in people over 40 years old, for an unlimited period of processing.
• the invention also relates to the methods of treatment of the abovementioned pathologies, by administration to the patients likely to be treated, of the abovementioned antifungal agents, in particular at the doses indicated above, and during the abovementioned durations.
• the abovementioned antifungals are used, in the context of the present invention, for the preparation of medicaments capable of being administered orally, in particular in the form of tablets or oral suspensions, or by injectable route.
• the invention will be further illustrated with the aid of the following detailed description of the demonstration of fungi as defined above in biposias of human origin.
• the materials collected during the biopsies are " 137 in number, distributed according to their gender between: aorta 35; saphenous vein 30; carotid artery 17; mammary artery 39; pulmonary artery, radial artery, etc. 6.
• the smears were prepared as follows: a small piece of biological material was placed between two slides. It is allowed to dry and then the slides are fixed using heat. From each biopsy, a Gram-colored smear is prepared - Modification of Bôzuc: staining with violet crystal and carbon nitrate, lugol; discoloration with acetone alcohol and obtaining the contrast with safranine. The smear thus colored is observed under the immersion microscope under objective x 100. Another smear is prepared for observation under fluorescence. 2.b. Seeding
• the microbiological inoculation is done on a solid nutritive medium of Sabouraud, while seeking to obtain a maximum contact of the biological material with the nutritive medium. For this, the solid medium is cut and the biological material is seeded in the cut obtained.
• the nutrient medium contains:
• the medium is sterilized for 10 minutes at 121 ° C.
• the Petri dishes are rolled up with a plaster to reduce the risk of contamination during the cultivation time.
• the culture of the material is done at 28 ° C for 30 days by carrying out daily checks without removing the sticking plaster from the Petri dishes.
• API 32C from Bio-Mérieux is used, which is used for yeasts, as well as macroscopic and microscopic observation methods used for the morphological identification of other types of mycelium.
• the time necessary for the clear appearance of a fungal colony is between the 4 th and the 20 th day after the primary seeding, with two climaxes: the 6 th and the 13 th day. From September 21 to October 6, out of 50 patients, 21 had biopsies with positive results (development of the strain), ie 42%. It is interesting to note that the percentage of strain development is 75% for patients who have had 4 biopsies, 70% for those who have had 3 biopsies and that this percentage drops to 29-26% for those who had 2 and 1 biopsies. By biopsy, the percentage of positive results is 28%.
• Rhodotorula The second type of fungal strain found according to its rate of presence in biological materials is Rhodotorula (Rubra, Glutinis). It grows directly from biological material while entering the environment. The identification of this strain was carried out by API 32C and it turned out that it is Rhodotorula Rubra and Rhodotorula Glutinis. Rhodotorula cases are distributed equally between patients in both hospitals. Rhodotorula grows faster, between 3 and 7 days from sowing. In the majority of cases, it grows from a patient's biopsy, where later the whitish filamentous strain will also grow, and represents 12% of patients. The third fungal strain based on its presence rate in biopsies was found to be Candida Lipolitica (on 2 patients).

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• 1998
  • 1998-10-27 AU AU10369/99A patent/AU1036999A/en not_active Abandoned
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• 1999
  • 1999-10-27 IL IL14264199A patent/IL142641A0/xx unknown
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  • 1999-10-27 EP EP99950850A patent/EP1124560A1/fr not_active Withdrawn
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