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Methods and compounds for the treatment of mucus hypersecretion

a technology of mucus hypersecretion and treatment method, which is applied in the direction of antibody medical ingredients, fusions for specific cell targeting, peptide/protein ingredients, etc., can solve the problems of small airway obstruction, slow forced lung emptying, and reduced maximal respiratory flow, so as to prevent the hypersecretion of copd, reduce mucus secretion, and treat mucus hypersecretion effectively

Inactive Publication Date: 2008-06-26
HEALTH PROTECTION AGENCY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]An advantage of the invention is that an agent for effective treatment of mucus hypersecretion and associated disease states is now provided and used, offering a relief to sufferers where hitherto there was no such agent available.
[0008]The present invention thus represents a new different approach to treatment of mucus hypersecretion by inhibiting secretory processes, namely one or other or both of the mucus secretion by mucus secretory cells and the secretion of neurotransmitters regulating mucus secretion. Agents of the present invention reduce mucus secretion and / or prevent the hypersecretion of COPD and asthma, and any other disease in which mucus hypersecretion is a causative element.

Problems solved by technology

The excessive, chronic bronchial secretion results in expectoration, and can last from a few days to many years.
The mucus hypersecretion of COPD results in small airway obstruction producing reduced maximal respiratory flow and slow forced lung emptying.
There is minimal reversal of the impaired airway function of COPD by bronchodilators and currently no effective therapy for the mucus hypersecretion.
The mucus hypersecretion component of asthma is not well controlled by current therapies, particularly in severe and chronic cases.

Method used

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  • Methods and compounds for the treatment of mucus hypersecretion
  • Methods and compounds for the treatment of mucus hypersecretion
  • Methods and compounds for the treatment of mucus hypersecretion

Examples

Experimental program
Comparison scheme
Effect test

example 1

Method for the Preparation of Substance P-LHN / A Conjugates

[0077]The lyophilised peptide was rehydrated in 0.1% trifluoroacetic acid (TFA) to a final concentration of 10 mM. Aliquots of this solution were stored at −20 degrees C. until use. The LHN / A was desalted into PBSE (PBS containing 1 mM EDTA). The resulting solution (3-5 mg / ml) was reacted with a three- or four-fold molar excess of SPDP by addition of a 10 mM stock solution of SPDP in DMSO. After 3 hours at room temperature the reaction was terminated by desalting over a PD-10 column into PBSE.

[0078]A portion of the derivatised LHN / A was removed from the solution and reduced with DTT (5 mM, 30 min). This sample was analysed spectrophotometrically at 280 nm and 343 nm to determine the degree of derivatisation. The degree of derivatisation achieved was typically 2 mol / mol.

[0079]The bulk of the derivatised LHN / A and the substance P peptide were mixed in proportions such that the peptide was in four-fold molar excess. The conjugat...

example 2

Method for the Preparation of a Broad Specificity Agent

[0087]Conjugation and purification of WGA-LHN / A. WGA (10 mg / ml in phosphate-buffered saline (PBS)) was reacted with an equal concentration of SPDP (10 mM in dimethyl sulphoxide (DMSO)) for one hour at ambient temperature. Reaction by-products were removed by desalting into PBS prior to reduction of the cross-linker with dithiothreitol. The thiopyridone and DTT were then removed by desalting into PBS to result in derivatised WGA (dWGA) with 1 mole—SH incorporated per mole of WGA.

[0088]LHN / A at a concentration of 3-5 mg / ml in PBSE (PBS containing 1 mM EDTA) was reacted with a three or four-fold molar excess of SPDP (10 mM in DMSO). After 3 h at ambient temperature the reaction was terminated by desalting over a PD-10 column into PBSE.

[0089]The derivatised WGA (dWGA) and the derivatised LHN / A (dLHN / A) were mixed in a 3:1 molar ratio. After 16 h at 4° C. the mixture was centrifuged to clear any precipitate that had developed. The su...

example 3

Preparation and Maintenance of Neuronal Cultures and Inhibition of Neurotransmitter Release

[0091]PC12 cells were seeded at a density of 4×105 cells / well onto 24 well (matrigel coated) plates (NUNC™) from stocks grown in suspension. The cells were cultured for 1 week prior to use in RPMI, 10% horse serum, 5% foetal bovine serum, 1% L-glutamine. SH-SY5Y cells were seeded at a density of 5×105 cells / well onto 24 well plates (FALCON™). The cells were cultured in HAM-F12:MEM (1:1 v / v), 15% foetal bovine serum, 1% MEM non-essential amino acids, 2 mM L-glutamine for 1 week prior to use. Embryonic spinal cord (eSC) neurons were prepared from spinal cords dissected from 14-15 day old foetal Sprague Dawley rats and were used after 21 days in culture using a modification of previously described method.

[0092]Inhibition of transmitter release. PC12 cells or SH-SY5Y cells were washed with a balanced salt solution (BSS: 137 mM NaCl, 5 mM KCl, 2 mM CaCl2, 4.2 mM NaHCO3, 1.2 mM MgCl2, 0.44 mM KH2PO4...

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Abstract

A method of treating mucus hypersecretion, the causative factor in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD, comprises administering a compound that inhibits exocytosis in mucus secreting cells or neurones that control or direct mucus secretion. Also described is a compound, for use in the treatment of hypersecretion of mucus, which inhibits mucus secretion by inhibiting mucus secretion by mucus secreting cells, and / or inhibiting neurotransmitter release from neuronal cells controlling or directing mucus secretion.

Description

1. FIELD OF THE INVENTION[0001]The present invention relates to treatment of mucus hypersecretion, to compositions therefor and manufacture of those compositions. The present invention relates particularly, though not exclusively, to the treatment of chronic bronchitis in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD.2. DESCRIPTION OF RELATED ART[0002]Mucus is a thin film of protective viscoelastic liquid which lines the airways. It is a 1-2% aqueous solution, in which the major components are the glycoconjugates known as mucins. Mucus, including the mucins, is secreted by mucus secretory cells, the surface epithelial goblet cells of the large airways and the mucus cells of the submucosal glands. Mucin release occurs by three mechanisms: constitutive secretion, regulated secretion and protease cell surface activity. Of these it is regulated secretion that responds to external stimuli and is amenable to therapeutic intervention in C...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/08A61K39/00C12N15/63A61P25/00A61K47/48
CPCA61K38/4886C07K2319/33C07K14/33A61K47/48238A61K47/62A61P25/00
Inventor QUINN, CONRAD PADRAIGFOSTER, KEITH ALANCHADDOCK, JOHN
Owner HEALTH PROTECTION AGENCY
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