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Composition for the treatment of digestive pathologies

A therapeutic, digestive disorder technology, applied in the composition of paracellular permeability, hyperalgesia and other abdominal pain, bowel dysfunction, irritable bowel syndrome, which can solve unrecognized problems

Inactive Publication Date: 2007-02-07
RYTEK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these preliminary findings have not yet been confirmed or led to new treatments

Method used

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  • Composition for the treatment of digestive pathologies
  • Composition for the treatment of digestive pathologies
  • Composition for the treatment of digestive pathologies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Reduction of rectal hyperalgesia by tight junction blockers.

[0046] The intestinal epithelium contains structures connecting epithelial cells that ensure the controlled passage of immune cells into the intestinal submucosa. This example shows that some molecules known to increase the paracellular permeability of the intestine, such as SLIGRL, promote the accumulation of immune cells (mast cells, enterochromaffin cells) in the submucosa of the intestine, and by blocking Intracolonic treatment of the agent can prevent (eg, inhibit, reduce) this effect.

[0047] Six groups of 8 male Wistar rats (200-250 g) each were used in this study. The animals were equipped with an indwelling intracolic catheter in the proximal colon (3 cm from the cecum-colon junction). In these experiments, four groups of rats received 10 hours of 51 Cr-EDTA (0.5μC / h) was infused into the colon. Animals were placed in different cages and urine was collected for 24 hours. Measurement...

Embodiment 2

[0048] Example 2: Paracellular permeability in mouse colon. Effect of different bacterial protease inhibitors.

[0049] Six groups of 10 male Swiss mice (25-30 g) each were used for this study. Animals received 5 hours of intracolonic infusion (250 μl / h) of different protease inhibitor solutions through a catheter inserted into the rectum and fixed at the base of the tail; 51 Cr-EDTA was added to the infusion solution ( figure 2 ). At t=5 hours, the animals were sacrificed, the colons were removed, and the total radioactivity remaining in vivo was taken as an index of paracellular permeability. Paracellular permeability was improved after infusion of protease inhibitor cocktail (Roche ref.: 1,873,580, EDTA-free), serine protease inhibitors (aprotinin, Sigma A 1153) and nonspecific matrix metalloproteinase inhibitors (garlardin, Sigma: M5939.) After significantly lower ( figure 2 ).

Embodiment 3

[0050] Example 3: Changes in the paracellular permeability of the colon of mice induced by intraluminal infusion of insulin and supernatant of colonic contents, and after treatment with a cocktail of antibiotics.

[0051] Groups of 10 male Swiss mice (Janvier-France) each weighing 25-30 g were used for this study. The effects of intracolonic infusion of insulin (50 μL, 600 U) and the supernatant of colon contents from control mice on the paracellular permeability of the colon were evaluated under baseline conditions, and were performed on one day (D1) or two consecutive days ( D2) Intracolonic infusion (250 μl / h) was administered for 3 hours. The same infusion was then repeated 12 days after treatment with an oral antibiotic cocktail (Neomycin 2 mg / kg / day + Ampicillin 1 mg / kg / day). The results showed that: 1) antibiotic treatment decreased colonic permeability, 2) the increase in permeability caused by insulin disappeared after antibiotic treatment, which may cause the loss o...

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Abstract

Use of at least one protease inhibitor (I) to prepare a composition for preventative or curative treatment of intestinal disorders characterized by hyperalgesia. - An INDEPENDENT CLAIM is also included for a pharmaceutical product (A) containing at least one (I) and at least one other agent (II), i.e. an anticholinergic, prokinetic or antidiarrhea agent; laxative; modifier of motility or of viscero-sensitivity, for combined use, separately or sequentially. - ACTIVITY - Analgesic; Antiinflammatory. - MECHANISM OF ACTION - (I) control (reduce) the paracellular permeability of the intestinal epithelium, by controlling the light junctions, and associated pain. Proteases, produced by bacteria in the colon, activate receptors in the membrane of epithelial cells that modulate opening of these junctions, where opening is responsible for hyperalgesia. Mice were perfused, through the colon, with 250 mu l / hour of a solution of protease inhibitors, labeled with 51-chromium-EDTA. After 5 hours, the colons were removed and the amount of bound radioactivity measured as an indicator of paracellular permeability. For a control, retention of radioactivity was about 2.1%; compare about 1.1% following perfusion with a cocktail of protease inhibitors (or with serine protease or matrix metalloprotease inhibitors).

Description

technical field [0001] The present invention relates to compositions and methods for treating intestinal disorders. The present invention also relates to compositions and methods useful for modulating the paracellular permeability of the intestinal epithelium. The compositions and methods of the invention are based inter alia on the use of those protease inhibitors that regulate the opening of the tight junctions of the intestinal epithelium. The present invention can be used for the prophylactic or therapeutic treatment of different conditions in mammals, especially humans, such as digestive tract (gastrointestinal) disorders (TFD), more specifically intestinal disorders (TFI), especially irritable bowel Syndrome (SII), hyperalgesia and other abdominal pain. Background technique [0002] The intestinal epithelium is a very important place for exchange between external media and the body. The exchange can occur across epithelial cells, or through parallel networks. For e...

Claims

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Application Information

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IPC IPC(8): A61K38/55A61P1/00
CPCA61K38/57A61K31/405A61K31/00A61K9/00A61P1/00A61P1/04A61P1/10A61P1/12A61P25/02A61P29/00A61P43/00A61K38/55
Inventor 利昂内尔·布埃诺
Owner RYTEK
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