Nitric oxide synthase inhibitors for inhibiting the production o

Details Nitric oxide synthase inhibitors for inhibiting the production o Nitric oxide synthase inhibitors for inhibiting the production o

1997-04-11

1999-01-12

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

A61K 31195

Patent

active

058590587

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of nitric oxide synthase inhibitors in inhibiting secretion and/or production of airway mucus, in particular in treating chronic bronchitis, cystic fibrosis and bronchorrhea.
In cystic fibrosis several functions of airway epithelia are abnormal including thickened airway surface fluid. This thickened airway fluid contributes to the recurrent pulmonary infections and loss of ventilatory function that occur in cystic fibrosis. Retained airway secretions are also known to contribute to the morbidity of other pulmonary diseases such as asthma and chronic obstructive pulmonary disease.
The therapeutic goal in cystic fibrosis and other pulmonary diseases in which the water content of the mucus is altered is to remove retained secretions from the lungs. For example, the use of aerosolised amiloride to facilitate the removal of retained mucus secretions is described in U.S. Pat. No. 4,501,729. Amiloride appears to block Na.sup.+ reabsorption by airway epithelial cells, and therefore inhibits water absorption from mucus.
A different therapeutic approach is to increase the water content of the airway surface liquid by modulating the activity of chloride channels. An example of this is the administration of ATP or UTP, which appear to induce hydrated mucus secretions by stimulating chloride secretion from respiratory epithelial cells. See, e.g., C.Stock, Breathing Easier: A promising Treatment for Cystic Fibrosis, Endeavors, 10, 10-11 (Fall 1992) (Published by the Office of Research Services, The University of North Carolina at Chapel Hill).
It has subsequently been found that administering a nitric oxide synthase inhibitor is beneficial in inhibiting the production and/or secretion of airway mucus.
Accordingly, the present invention provides a method of inhibiting the production and/or secretion of airway mucus which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the lungs of the mammal.
In a further aspect, the present invention provides a method of combating cystic fibrosis which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
In a yet further aspect, the present invention provides a method of combating excessive mucus production in chronic bronchitis which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
In a still further aspect the present invention provides a method of combating emphysema which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
The method of the present invention may further comprise the step of concurrently administering a further active agent useful in improving mucociliary clearance of airway mucus, for example a sodium channel blocker, such as amiloride, in an amount effective to inhibit the reabsorption of water from lung mucus secretions, or a lantibiotic such as duramycin, or a nucleotide such as adenosine triphosphate (ATP) or uridine triphosphate (UTP) in an amount effective to facilitate hydration and clearance of airway mucus.
In the alternative there is provided the use of a NO synthase inhibitor in the manufacture of a medicament to facilitate mucus clearance
The present invention also provides the use of an NO synthase inhibitor for the manufacture of a medicament for the inhibition of the production of airway mucus in a patient in need of such treatment. Suitably the patient is suffering from cystic fibrosis or chronic bronchitis.
Suitably the NO synthase inhibitor is an arginine derivative such as those described in U.S. Pat. No. 5,028,627 and preferably it is N.sup.G -monomethyl-L-arginine (L-NMMA) or a salt thereof.
L-NMMA is available from Sigma Chemical Company Limited, Fancy Road, Poole, Dorset BH17 7NH, England.
Many NO synthase inhibitors, for example L-NMMA, are capable of forming salts. Thus, the present invention includes NO synthase inhibitors in the form of salts, in particular

REFERENCES:
patent: 5028627 (1991-07-01), Kilbourn et al.
patent: 5317040 (1994-05-01), Goldman
patent: 5358969 (1994-10-01), Williamson et al.
"Neural nitric oxide synthase is localized in extrinsic nerves regulating perireceptor processes in the chemosensory nasal mucosae of rats and humans", J. Comp. Neurol., vol.. 345, No. 1, pp. 125-138, Jul. 1, 1994.
"TNF-alpha stimulates mucin secretion and gene expression in airway epithelium in vitro", Chest, vol., 107, No. 3, pp. 133S-135S, Mar. 3, 1995.
"Impairment of endothelium-dependent pulmonary artery relaxation in chronic obstructive lung disease", N. Engl. J. Med., vol. 324, No. 22, pp. 1539-1547 (1991).

Affiliated with

Also associated with

Rating

Nitric oxide synthase inhibitors for inhibiting the production o does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Nitric oxide synthase inhibitors for inhibiting the production o, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitric oxide synthase inhibitors for inhibiting the production o will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1516514