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Treating infectious diseases using ice inhibitors

An inhibitor and subject technology, applied in sensory diseases, anti-infective drugs, anti-infective drugs, etc., can solve the problems of inability to release IL-1β, and ICE inhibitors do not show

Inactive Publication Date: 2007-01-24
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While other proteases, including bacterial and host proteases, can process pro-IL-1β, ICE-deficient (ICE - / - ) mice have been shown to be unable to release mature IL-1β in response to endotoxin (Fantuzzi et al., 1997; Li et al., 1995)
[0009] However, ICE inhibitors have not been shown to be effective in treating specific diseases such as bacterial keratitis

Method used

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  • Treating infectious diseases using ice inhibitors
  • Treating infectious diseases using ice inhibitors
  • Treating infectious diseases using ice inhibitors

Examples

Experimental program
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preparation example Construction

[0076] A description of the preparation and administration of ophthalmic and other formulations can be found in Remington: The Science and Practice of Pharmacy (formerly Remington's Pharmaceutical Sciences).

[0077] The compounds and compositions described above are also useful in therapeutic applications in connection with certain infectious diseases.

[0078] The compounds of the present invention inhibit the release of IL-1 β and / or IL-18 and are thus useful for inhibiting or blocking several of the pathophysiological effects of certain diseases presented herein.

[0079]The present invention also relates to a method by (1) inhibiting the release of IL-1β and / or IL-18 from cells and / or (2) preventing excessive tissue levels of IL-1β and / or IL-18 in mammals, including humans. Therapeutic methods for the treatment of specific diseases by the adverse, toxic or lethal effects of 18. The method comprises administering to the mammal an ICE-inhibiting effective amount of one or ...

Embodiment 1

[0105] animal infection

[0106] Eight-week-old female B6 mice (The Jackson Laboratory, Bar Harbor, ME) were used in these experiments. Under a stereomicroscope, using a sterile 255 / 8 gauge needle, puncture the left cornea of ​​each anesthetized mouse with three parallel 1 mm incisions. Use 1.0×10 6 CFU / μl of Pseudomonas aeruginosa (5 μl dose, ATCC strain 19660 or clinical isolate-1025 or ciprofloxacin-resistant 19660 strain (Kwon and Hazlett, 1997) as previously described) to locally challenge the scratched cornea . On day 1 post-infection (p.i.) and at the following times, eyes were inspected visually to ensure that all mice were similarly infected and to monitor the course of the disease. All animals were handled humanely and the use and handling of the animals in the research fully complied with the resolutions of the Association for Research in Vision and Ophthalmology.

Embodiment 2

[0108] bacterial strain

[0109] Pseudomonas aeruginosa strain 19660 was used as a standard laboratory strain and produced reproducible corneal lesions in the B6 mouse model (Kernacki et al., 2000; Rudner et al., 2000). In 1999, Pseudomonas aeruginosa strain 1025 (KEI-1025) was isolated from a human case of microbial keratitis at the Kresge Eye Institute, Detroit, MI. Laboratory-derived ciprofloxacin-resistant mutants were obtained by serial passage of wild-type Pseudomonas aeruginosa strain 19660 in Luria-Bertani (LB) broth containing ciprofloxacin developed for resistance (Sanchez et al., 2002). Ciprofloxacin-resistant Pseudomonas aeruginosa strains showed a 100-fold increase in the minimum inhibitory concentration (MIC) of ciprofloxacin required to kill the bacteria in vitro compared to the parental strain (0.25 mg / ml versus 25mg / ml). During in vitro production of this mutant, the ciprofloxacin-resistant (Pseudomonas aeruginosa 19660) mutant was less virulent than the pa...

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Abstract

This invention relates to methods and compositions for treating infectious and other diseases, particularly of the eye, by administering an ICE inhibitor. This invention also relates to methods for treating injuries, allergies, chemical irritations, or burns of the eye by administering an ICE inhibitor.

Description

technical field [0001] The present invention relates to methods and compositions for treating infections and other diseases and conditions using ICE inhibitors. Background technique [0002] Pseudomonas aeruginosa (P. aeruginosa) keratitis is a vision-threatening disease of the cornea that accounts for about 3 / 4 of the reported cases of microbial infection associated with contact lenses (Liesegang, 1997). Left untreated, the disease progresses rapidly, causing corneal ulceration and potentially permanent vision loss due to corneal scarring (Laibson, 1972). Tissue damage during Pseudomonas keratitis can occur due to a variety of microbial (Engel et al., 1998; Kernacki et al., 1995) and host-related factors (Steuhl et al., 1987; Steuhl et al., 1989). However, host inflammatory responses have been shown experimentally to play an important role in the outcome of P. ; Rudner et al., 2000; Thakur et al., 2002; Xue et al., 2003a; Xue et al., 2003b). [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/551A61K31/4025A61K31/4015A61K38/05A61K38/06A61P31/00A61P33/00A61K31/5513A61K38/04A61K38/55A61K45/06
CPCA61K9/0048A61K45/06A61K31/00A61K31/551A61K38/55A61K31/5513A61K31/4015A61K38/06A61K38/05A61K31/4025A61P27/02A61P27/14A61P31/00A61P31/04A61P31/10A61P31/12A61P33/00A61K2300/00
Inventor J·C·R·兰德尔G·库L·哈兹勒特
Owner VERTEX PHARMA INC