Methods of hydrating mucosal surfaces

Details Methods of hydrating mucosal surfaces Methods of hydrating mucosal surfaces

1999-10-20

2001-07-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C514S255030

Reexamination Certificate

active

06264975

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns methods of hydrating nasal airway surfaces in patients in need of such treatment, along with compounds and compositions usefull for carrying out such methods.
BACKGROUND OF THE INVENTION
The current therapy for hydrating nasal airway surfaces is to apply normal saline via drops or spray delivery devices. The disadvantage of this simple approach is that the duration of effect is short. It would be desireable to provide a way to achieve a more lasting hydration of nasal airway surfaces.
U.S. Pat. No. 5,789,391 to Jacobus describes methods of treating sinusitis with uridine triphosphates and related compounds such as UTP or P
1
,P
4
-di(uridine-5′ tetraphosphate (U
2
P
4
) in an amount effective to promote drainage of congested fluid in the sinuses by hydrating mucous secretions or by stimulating ciliary beat frequency in the sinuses.
U.S. Pat. No. 4,501,729 to Boucher describes the use of respirable or non-respirable amiloride to hydrate airway mucous secretions, and U.S. Pat. No. 5,656,256 to Boucher and Stutts describes the use of respirable or non-respirable benzamil and phenamil to hydrate lung mucous secretions. The use of amiloride, benzamil or phenamil to hydrate nasal airway surfaces is neither disclosed nor suggested.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of hydrating nasal airway surfaces in a subject in need of such treatment. The method comprises topically applying a sodium channel blocker to a nasal airway surface of the subject in an amount effective to inhibit the reabsorption of water by the nasal airway surface. The channel blocker may be a pyrazinoylguanidine sodium channel blocker, such as benzamil, phenamil, amiloride, or a pharmaceutically acceptable salt thereof.
The method may further comprise the step of topically applying a P2Y
2
receptor agonist to a nasal airway surface of the subject in an amount effective to stimulate chloride secretion, and thereby stimulate water secretion, by the nasal airway surface.
A second aspect of the present invention is a method of hydrating mucosal surfaces such as airway surfaces in a subject in need of such treatment, comprising topically applying a sodium channel blocker to a mucosal surface such as an airway surface of the subject in an amount effective to inhibit the reabsorption of water by the surface, wherein the sodium channel blocker is a covalent conjugate of a pyrazinoylguanidine sodium channel blocker and a non-absorbable carrier moiety (e.g., polyethylene glycol, albumin; carbohydrate).
Again, the method may further comprise the step of topically applying a P2Y
2
receptor agonist to a mucosal surface such as an airway surface of the subject in an amount effective to stimulate chloride secretion by the surface.
A third aspect of the present invention is a pharmaceutical formulation, comprising a sodium channel blocker in a pharmaceutically acceptable carrier (e.g., an aqueous carrier solution); wherein the sodium channel blocker is a covalent conjugate of a pyrazinoylguanidine sodium channel blocker and a non-absorbable carrier moiety; preferably subject to the proviso that the non-absorbable carrier moiety is not bovine serum albumin or rabbit serum albumin. The composition may further contain a P2Y
2
receptor agonist.
A fourth aspect of the present invention is a compound useful as a sodium channel blocker, the compound comprising a covalent conjugate of a pyrazinoylguanidine sodium channel blocker and a non-absorbable carrier moiety; preferably subject to the proviso that the non-absorbable carrier moiety is not bovine serum albumin, rabbit serum albumin or agarose. For example, the carrier moiety can be polyethylene glycol or human serum albumin, or a carbohydrate.
A fifth aspect of the present invention is the use of compounds as described above for the preparation of a medicament for the treatment of disorders as described herein.


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Benos et al., Purification and characterization of the amiloride-sensitive sodium channel from A6 cultured cells and bovine renal papilla,Proc. Natl. Acad. Sci. USA,83:8525-8529 (1986).
Kleyman et al., New amiloride analogue as hapten to raise anti-amiloride antibodies,Am. J. Physiol,250 (Cell Physiol. 19):C165-C170 (1986).
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