Classifications

• • 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
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • 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
  • A61P11/12—Mucolytics
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • 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
• • 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
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

Definitions

• the subject of the invention is pharmaceutical and / or dietetic compositions, based on an enzyme or an enzymatic complex containing this enzyme, which can contribute to the prevention and / or treatment of diseases.
• compositions based on an enzyme or an enzymatic complex containing this enzyme stimulating the functions of the intestine and thus being able to contribute to the prevention and / or the treatment of degenerative diseases linked to aging.
• This filamentous bacterium can simultaneously produce at least 5 proteinases and 2 peptidases, these 7 enzymes have been described by K MORIHARA et al (Biochim Biophys Acta, 1967, 139, 382) When they are added together in the food consumed by animals, these 7 enzymes cause an excessive reduction in the viscosity of the intestinal mucus, and can then cause an ulceration of the intestinal wall These 7 enzymes therefore have negative effects in animal husbandry when used together Under the conditions indicated in the aforementioned patent, PANSTIMASE® is obtained, which consists only of 3 exocellular proteinases, with a preponderance of one of them, and excluding endocellular proteinases and peptidases. When added to food consumed by animals, PANSTIMASE® causes a moderate reduction in the viscosity of intestinal mucus, and is not likely to attack the intestinal wall.
• PANSTIMASE® exerts a stronger action on the proteins of raw materials used in the composition of food, which improves their digestibility.
• PANSTIMASE® exerts indirect actions on the various organs, in particular on the pancreas; as already indicated in the prior patent, it has been found that it causes an increase of 50 to 80% in the concentration of enzymes or proenzymes in this organ.
• PANSTIMASE® is now used as a nutritional supplement added to animal feed, to improve their growth or productivity. It has thus been found that it also improves the resistance of animals to infectious, bacterial or viral diseases, and that it reduces certain negative effects of aging.
• compositions require additional purification compared to the product used for the animal. Under the conditions indicated in the previous patent, an unpurified PANSTIMASE® is obtained, the titer of which is at least equal to 2,000 AU / mg.
• the Anson Unit (abbreviated AU) is here defined as the quantity of enzyme which, incubated for 10 min at 25 ° C. and at pH 7.5 in the presence of denatured hemoglobin, releases of this substrate the equivalent of 1 mcg of tyrosine, determined by spectrophotometric absorption at 280 nm on the filtrate which cannot be precipitated by trichloroacetic acid.
• This preponderant proteinase alone explains the main physiological properties of PANSTIMASE®, due in particular to the fact that it alone exerts a characteristic action on two important proteins: cholera toxin and collagen.
• Cholera toxin is the counterpart of the LT toxin produced by certain pathogenic colibacilli; it is composed of the A subunit which is aggressive, and the B subunit which is immunostimulatory. At a low concentration, comparable to that which exists in the intestine of animals receiving a food supplemented with PANSTIMASE®, the preponderant proteinase selectively destroys the A subunit without destroying the B subunit which thus retains its capacity to stimulate the immune system .
• Collagen is the most abundant protein in the animal kingdom: in mammals, the different types of collagen represent about a third of total proteins. We know that the solubility of muscle collagen in hot water is high if it comes from young animals, and low if it comes from old animals.
• the subject of the present invention is pharmaceutical and / or dietetic compositions containing, as active principle, the preponderant exocellular proteinase produced by culturing Streptomyces fradiae having a specific activity greater than 100,000 AU / mg, a molecular weight varying from 30 to 36 kDa and preferably close to 32 kDa, an isoelectric point close to 7.0, and capable of selectively destroying the cholera toxin A subunit without destroying the B subunit, in mixture or in association with an excipient or an inert vehicle , non-toxic, physiologically acceptable.
• the preponderant exocellular proteinase produced by culturing Streptomyces fradiae having a specific activity greater than 100,000 AU / mg, a molecular weight varying from 30 to 36 kDa and preferably close to 32 kDa, an isoelectric point close to 7.0, and capable of selectively destroying the cholera toxin A subunit without destroying the B subunit
• the present invention also relates to pharmaceutical and / or dietetic compositions containing, as active principle, the preponderant exocellular proteinase as defined, or the mixture of this preponderant exocellular proteinase with at least one of the other two exocellular proteinases produced by in culture of Streptomyces fradiae, or, one or more proteinases whose amino acid sequences have at least 60% homology with those of the predominant exocellular proteinase or with those of the mixture of proteinases as defined above, in mixture or in combination with an inert, non-toxic, physiologically acceptable excipient or vehicle.
• the homologous proteinases can be extracted from the culture of different microorganisms and in particular from Streptomyces fradiae or Streptomyces griseus.
• the active ingredient is administered by oral, pulmonary or genital route in doses between 5,000 and 100,000 AU.
• the active principle is put, in a mixture or in association with conventional excipients, in one of the pharmaceutical forms suitable for these types of administration.
• the active ingredient is presented in particular in one of the usual forms in pharmacotechnology such as tablets, sugared almonds, capsules, capsules, powders, solutions or suspensions, dry aerosols, ova, vaginal tablets
• Administration will be based on therapeutic need, one to three times a day
• PANSTIMASE® which acts directly in the intestine, can act indirectly
• the intestine is also the organ richest in immune cells, which circulate in its blood and lymphatic vessels, or which gather and multiply in the plates of PEYER
• immune cells are a component of MALT (Mucosae Associated Lymphoid Tissue) which is subdivided into GALT located in the intestine, and BALT located in the bronchi, and which presents analogies with SALT located in the skin GALT and BALT are interdependent and act in synergy to ensure the immune defense of the mucous membranes, and to contribute to the defense of the organism as a whole
• E G F epithelial Growth Factor
• the intestinal secretions can contain growth factors capable of acting on enterocytes, lymphocytes.
• PANSTIMASE® may explain the better development of the villi and of the GALT, observed on the histological sections of the intestine of the treated rats.
• PEYER plaques which are aggregates of immune cells distributed throughout the intestine, are more numerous in treated rats. They appear from the duodenum in these rats, but only from the jejunum in the control rats, they are also more dense. their lymphocytes are smaller, tighter, and seem more active (they are more intensely stained by the reagents used in histology)
• Non-prolonged adhesion of infectious germs PANSTIMASE® can oppose the prolonged adhesion of infectious germs on the mucous membranes, and in particular on the intestinal mucosa.
• adhesins and receptors are complex (glyco-lipo) proteins.
• ANS PANSTIMASE® can stimulate the renewal of the villi in the intestine, that is to say the elimination of old cells which are abnormal or affected by the adhesion of infectious germs; this elimination is facilitated by the intensification of the flow of intestinal secretions, the production of which is increased under the action of PANSTIMASE®.
• PANSTIMASE® can first allow a closer contact between the infectious germs and the intestinal mucosa (and induce the multiplication in the intestine of immune cells able to fight against these germs), it can also then oppose the prolonged adhesion of these germs to the mucosa and their penetration into the underlying tissue.
• PANSTIMASE® destroys many protein toxins, and can thus contribute to the prevention and / or treatment of diarrhea.
• toxins destroyed by PANSTIMASE® we can cite the botulinum toxin, cholera toxin, LT toxin produced by pathogenic colibacilli, the Necrotizing Cytotoxic Factor also produced by these colibacilli ...
• PANSTIMASE® exerts, throughout the intestine, a fundamental action which stimulates the global functioning of this key organ, and consequently of the whole organism, hence the great diversity of examples of therapeutic applications
• Cystic fibrosis is characterized by the excessive secretion of excessively viscous mucus, in the intestine as in the bronchial level All mucus have the same type of biochemical structure, this is why PANSTIMASE® can optimize the viscosity of the intestinal mucus of the bronchial mucus or genital mucus
• exocellular proteinase (s) according to the invention or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the exocellular proteinase (s) of the invention, can be used for the manufacture of a drug intended to optimize the viscosity of intestinal, bronchial and / or genital mucus
• exocellular proteinase (s) according to the invention can be used for the manufacture of a drug intended for the treatment of cystic fibrosis and diseases related to an excess of secretion of an intestinal, bronchial and / or genital mucus, and in particular when this is too viscous
• PANSTIMASE® By its moderate detergent action on the intestinal wall, PANSTIMASE® contributes to improving absorption
• exocellular proteinase (s) according to the invention, or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the protein (s) exocellular proteinases of the invention, can be used for the manufacture of a medicament intended for the treatment of malabsorption of medicaments or nutrients, as well as for the treatment of disorders of the blood circulation, in particular, this medicament is intended for the treatment of undernutrition found in the elderly or in patients who have received drugs whose side effects affect the proper functioning of the intestine
• PANSTIMASE® opposes the prolonged adhesion of infectious germs on the mucous membranes and destroys many enterotoxins, it can thus help stimulate the renewal of the intestine and can prevent and / or treat digestive ulcers and enterotoxemias
• PANSTIMASE® is capable of reducing the number of pigs suffering from digestive ulcers, as well as the mortality from enterotoxemia
• exocellular proteinase (s) according to the invention, or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the exocellular proteinase (s) of the invention, can be used for the manufacture of a medicine intended to prevent and / or treat the prolonged adhesion of infectious germs on the mucous membranes, to facilitate the regeneration of atrophied or destroyed villi of the intestinal mucosa, as well as to prevent and / or treat digestive ulcers and enterotoxemias
• exocellular proteinase (s) according to the invention or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the exocellular proteinase (s) of the invention, can be used for the manufacture of a medicine intended to prevent and / or treat diabetes, liver failure and intestinal transit disorders.
• PANSTIMASE® acts favorably on GALT, and consequently on the whole immune system. This results in improvements in 3 different areas.
• the viral infection observed during a test at an experimental station was the subject of precise observations, covering a total of 120 kids, the percentage of animals not affected was 34% for the control group, and 70% for the treated group, the percentage of animals very affected was 28% for the control group, while no animal was very affected in the treated group
• PANSTIMASE® increases the number and density of PEYER plaques, which are aggregates of immune cells distributed throughout the intestine.
• PANSTIMASE® reduced the duration of arthritis which are inflammatory reactions following injuries to the joints affecting animals reared on metal gratings. After healing of the wounds, these inflammatory reactions can gradually fade under the action of so-called suppressive immune cells, which are numerous in the intestine, and which can migrate to areas of inflammation It is possible that PANSTIMASE® stimulates the multiplication of these cells in the intestine, and that '' facilitates their migration, which would explain the fact that it reduces the duration of arthritis by about 50%
• the improvements in health observed in intensive farming can be explained by a better response to vaccinations in animals receiving a feed supplemented with PANSTIMASE®
• Preliminary laboratory tests on mice have effectively confirmed that PANSTIMASE® can increase the effectiveness of vaccinations, especially when they are given orally
• the exocellular proteinase (s) according to the invention, or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the exocellular proteinase (s) of the invention can be used for the manufacture of a medicine intended to prevent and / or treat infectious diseases and immune dysfunctions, as well as to increase the effectiveness of vaccinations.
• PANSTIMASE® has been found to reduce the weaning-fertilizing interval (which tends to increase in sows), and to stimulate sexual drive, (which tends to decline in older pigs in older breeding pigs). boars). It thus appears that PANSTIMASE® makes it possible to remedy hormonal insufficiencies, and probably with other negative effects due to aging.
• PANSTIMASE® has been shown to cause "rejuvenation" in older breeding rats and a reduction in the negative effects of aging in older breeding sows and chickens.
• the first projection of the rats is normally affected around the age of 70 days; when performed around 140 days, the reproductive performance is poor for the control batch and is better for the treated batch (receiving the same food supplemented with 300 mg / kg of PANSTIMASE® grading 400 AU / mg).
• sows Breeding sows are culled as soon as they appear in "poor condition", for example when the farmer feels that they can no longer stand well, or lie down flexibly (instead of dropping heavily in may crush newborn piglets).
• sows are culled after 4.4 breeding cycles on average; six months after this use, it appeared that sows could be culled after 5.8 breeding cycles on average.
• PANSTIMASE® has made it possible to extend the productive life of sows by around 30%, without unacceptable alteration of their “good condition” and their performance.
• exocellular proteinase (s) according to the invention can be used for the manufacture of a medicine intended to prevent and / or treat hormonal insufficiencies and degenerative diseases linked to aging, for example arthritis, osteoarthritis, osteoporosis.
• PANSTIMASE® has no toxicity on piglets when administered for 1 month at a dose 20 times higher than the currently recommended use dose which is 40,000 AU. per kg of food, nor any toxicity on the rat when it is administered during 3 months at a dose 200 times higher than this dose of employment.
• a preliminary trial for cystic fibrosis was also initiated in an 18-year-old patient who received 2 capsules each containing 10,000 AU a day for 3 weeks.
• PANSTIMASE® there has been an improvement in symptoms, intestinal level (less abundant and less sticky faeces) and bronchial level (easier and less frequent sputum).
• exocellular proteinase (s) according to the invention or the proteinase (s) whose amino acid sequences have at least 60% homology with those of the exocellular proteinase (s) of the invention, can be used for the manufacture of a dietary composition for the food of the fragile or malnourished subjects.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
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• Diabetes (AREA)
• Gastroenterology & Hepatology (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Endocrinology (AREA)
• Epidemiology (AREA)
• Oncology (AREA)
• Pulmonology (AREA)
• Communicable Diseases (AREA)
• Reproductive Health (AREA)
• Nutrition Science (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)

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• 1996
  • 1996-04-05 FR FR9604310A patent/FR2747045B1/fr not_active Expired - Lifetime
• 1997
  • 1997-04-04 CA CA2251009A patent/CA2251009C/fr not_active Expired - Lifetime
  • 1997-04-04 RU RU98119950/14A patent/RU2198673C2/ru active
  • 1997-04-04 AP APAP/P/1998/001357A patent/AP1018A/en active
  • 1997-04-04 HU HU9902421A patent/HUP9902421A3/hu not_active Application Discontinuation
  • 1997-04-04 EP EP97919487A patent/EP0891189A1/fr not_active Ceased
  • 1997-04-04 CZ CZ0318598A patent/CZ298428B6/cs not_active IP Right Cessation
  • 1997-04-04 AU AU23938/97A patent/AU735340B2/en not_active Expired
  • 1997-04-04 NZ NZ332107A patent/NZ332107A/en unknown
  • 1997-04-04 PL PL97329161A patent/PL188157B1/pl not_active IP Right Cessation
  • 1997-04-04 TR TR1998/01976T patent/TR199801976T2/xx unknown
  • 1997-04-04 JP JP53591897A patent/JP4196225B2/ja not_active Expired - Lifetime
  • 1997-04-04 WO PCT/FR1997/000614 patent/WO1997037681A1/fr active IP Right Grant
  • 1997-04-04 BR BR9708506A patent/BR9708506A/pt not_active Application Discontinuation
  • 1997-04-04 CN CNB971952833A patent/CN1168499C/zh not_active Expired - Lifetime
• 1998
  • 1998-10-02 NO NO19984632A patent/NO324877B1/no not_active IP Right Cessation
  • 1998-10-05 OA OA9800190A patent/OA10894A/fr unknown
• 2000
  • 2000-11-20 US US09/717,808 patent/US6440413B1/en not_active Expired - Lifetime

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