Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • 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
  • A61P1/10—Laxatives
• • 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
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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

Definitions

• the intestinal epithelium is the center of very important exchanges between the external environment and the organism. These exchanges can take place either through the cells of the epithelium, or through parallel networks.
• the transport of water or electrolytes, or the absorption of small molecules (molecular weight generally less than about 1000 Da) at the level of the gastric, intestinal or colic mucosa is carried out by transcellular route, through epithelial cells or enterocytes.
• the absorption of large molecules and the passage of antigens, toxins or immune cells takes place mainly by the paracellular route, at the level of "tight junctions", which are arranged between the epithelial cells.
• abdominal pain without elimination disorder can be caused by food allergies or intolerances or manifest as part of celiac disease for example.
• Functional intestinal disorders affect 15 to 20% of the population and result in dyspeptic and / or intestinal symptoms for which no organic cause has so far been identified and which require specific treatment.
• the common characteristic of functional digestive disorders meeting ROME criteria is abdominal pain, present in the postprandial period, whether localized in the upper part (dyspepsia) or in the lower part of the abdomen.
• One particular disorder that affects the lower abdomen is Irritable Bowel Syndrome (SU). The pain of functional bowel disorders is most often relieved by defecation.
• SU Irritable Bowel Syndrome
• the present invention results from the demonstration of an in vivo role of tight junctions of the intestinal epithelium in the process of sensitization to pain.
• the "opening" of tight junctions of the colon epithelium by different molecules or by stress leads to spontaneous hyperalgesia or hypersensitivity to distension (characteristic state of 1TB S).
• the results obtained in the context of the present invention thus establish for the first time and surprisingly that the opening of tight junctions causes a state of lasting delayed hyperalgesia.
• the present invention also stems from the development of new therapeutic strategies for the treatment of intestinal pathologies, based on a modulation of the paracellular permeability of the intestinal epithelium.
• the present invention provides, for the first time, a therapeutic approach to intestinal pathologies based on the use of compounds or conditions making it possible to control the opening of tight junctions of the intestinal epithelium.
• these compounds or conditions make it possible to modulate the tension of the cytoskeleton of the intestinal epithelial cells or to directly regulate, preferably decrease, or even block, the opening of the tight junctions of the intestinal epithelium.
• This approach therefore makes it possible to control the opening and closing of the tight junctions of the intestinal epithelium, without necessarily resorting to de novo protein synthesis and / or to significant protein and / or structural degradations at the level of the epithelium.
• a first object of the invention therefore lies more particularly in the use of a compound controlling the opening of tight junctions of the intestinal epithelium, for the preparation of a medicament intended for the preventive or curative treatment of intestinal pathologies characterized by a state of hyperalgesia.
• Another object of the invention resides in a method of preventive or curative treatment of intestinal pathologies characterized by a state of hyperalgesia, comprising the administration to a subject of an effective amount of a compound controlling the opening of tight junctions of the intestinal epithelium.
• the compounds controlling the opening of the tight junctions of the intestinal epithelium are in particular compounds which modulate the tension of the cytoskeleton of intestinal epithelial cells or compounds which decrease, even block, the opening of the tight junctions of the intestinal epithelium.
• the reduction in the opening of tight junctions preferably corresponds to a minimum reduction of approximately 25%, advantageously of approximately 30%, even more preferably of approximately 50% of the paracellular permeability of the intestinal epithelium.
• Paracellular permeability can be measured using a marker such as 51 Cr-EDTA which, after passing through the blood, is measured in the urine for 24 hours (cf.: example 1).
• Another particular object of the invention resides in the use of a compound as defined above for the preparation of a medicament intended to reduce sensitization to allergens, pathogens and / or chemical molecules in affected or sensitive subjects functional intestinal diseases, in particular intestinal disorders characterized by an accumulation, in the submucosal layer, of immunocytes, in particular for example mast cells and / or enterochromaffin cells, by an increased sensitivity of the parietal mechanoreceptors and possibly by an infiltration of colon bacteria in the submucosal layer, for example hyperalgesia and in particular irritable bowel syndrome.
• functional intestinal diseases in particular intestinal disorders characterized by an accumulation, in the submucosal layer, of immunocytes, in particular for example mast cells and / or enterochromaffin cells, by an increased sensitivity of the parietal mechanoreceptors and possibly by an infiltration of colon bacteria in the submucosal layer, for example hyperalgesia and in particular irritable bowel syndrome.
• Figure 3 Suppression, using a “JS” blocker (TAP-100 mM), of rectal hypersensitivity to distension induced by SLIGRL (0.2 mg).
• Figure 9 Effect of ML-7 on the increase in permeability of tight epithelial junctions induced by taurocholate in rats.

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• Health & Medical 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)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2003
  • 2003-03-14 JP JP2003575946A patent/JP2005526772A/ja not_active Ceased
  • 2003-03-14 AU AU2003244690A patent/AU2003244690A1/en not_active Abandoned
  • 2003-03-14 US US10/504,087 patent/US7452877B2/en not_active Expired - Fee Related
  • 2003-03-14 EP EP03738170A patent/EP1485074A2/de not_active Withdrawn
  • 2003-03-14 WO PCT/FR2003/000831 patent/WO2003077893A2/fr not_active Ceased

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