Method of detecting lung disease

Details Method of detecting lung disease Method of detecting lung disease

1999-11-04

2001-04-10

Leary, Louise N. (Department: 1623)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S015000, C514S050000, C424S045000

Reexamination Certificate

active

06214536

ABSTRACT:

FIELD OF THE INVENTION
This application concerns lung diagnostic assays in general, and particularly concerns a lung diagnostic assay in which lung mucus secretions are hydrated to facilitate collection thereof.
BACKGROUND OF THE INVENTION
The analysis of sputum samples is particularly important in the treatment and diagnosis of many lung disorders, including lung cancer and tuberculosis (TB).
In particular, microbial infections of the lung are a serious problem in patients afflicted with acquired immune deficiency syndrome (AIDS). Two particularly problematic infections are
Pneumocystis carinii
pneumonia infections and mycobacterial infections.
Pneumocystis carinii
pneumonia infections are typically referred to as “PCP” infections. It is now estimated that approximately 70 percent of patients afflicted with AIDS will contract this disease. PCP may be treated with pentamidine isethionate, but an unfortunate side effect of this treatment is its toxicity. Accordingly, there is a continued need for techniques which permit the rapid and convenient screening of AIDS patients for this disease, and for the rapid, early, and accurate diagnosis thereof.
Mycobacteria are a large, diverse, and widely distributed family of aerobic, nonsporulating, nonmotile bacilli that have a high cell-wall lipid content and a slow growth rate. Some Mycobacteria are harmless, while others are significant pathogens. The pathogenic Mycobacterium include
M. tuberculosis
, responsible for tuberculosis, as well as non-tuberculosis Mycobacteria such as
M. avium
, responsible for
Mycobacterium Avium
complex infections.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of facilitating the obtaining of a mucus sample from at least one lung of a subject. The method comprises administering a physiologically acceptable salt to at least one lung of the subject in an amount effective to hydrate lung mucus secretions therein, and concurrently administering to said at least one lung of the subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat frequency therein, a compound of Formula (I) below, or a pharmaceutically acceptable salt thereof:
wherein:
X
1
, X
2
, and X
3
are each independently selected from the group consisting of OH and SH;
R
1
is selected from the group consisting of O, imido, methylene, and dihalomethylene; and
R
2
is selected from the group consisting of H and Br.
The method is accompanied or followed by the step of collecting a mucus sample from said at least one lung of said subject (e.g., by said subject expectorating a sputum sample).
Also disclosed is a method of facilitating the obtaining of a mucus sample from at least one lung of a subject, comprising administering to at least one lung of said subject, in an amount effective to hydrate lung mucous secretions, and/or stimulate mucus secretions therein, and/or stimulate ciliary beat frequency therein, a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereof, and then collecting a mucus sample from said at least one lung of said subject. The mucus samples collected may then be analyzed for the presence or absence of lung disease (e.g., microbial infection, cancer, etc.) in said subject.
A second aspect of the present invention is pharmaceutical composition useful for facilitating the collecting of a mucus sample from at least one lung of a subject, said composition comprising, alone or in combination, a physiologically acceptable salt in an amount effective to hydrate lung mucus secretions; and a compound of Formula (I) as given above, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucus secretions. The composition may be a liquid composition or a dry powder composition.
DETAILED DESCRIPTION OF THE INVENTION
Compounds illustrative of the compounds of Formula (I) above (also referred to as “active compounds” herein) include: (a) uridine 5′-triphosphate (UTP); (b) uridine 5′-O-(3-thiotriphosphate) (UTP&ggr;S); and (c) 5-bromouridine 5′-triphosphate (5-BrUTP). One preferred compound of Formula (I) above is the UTP analog uridine 5′-O-(3-thiotriphosphate) (or “UTP&ggr;S”). These compounds are known or may be made in accordance with known procedures, or variations thereof which will be apparent to those skilled in the art. See generally U.S. Pat. No. 5,292,498 to Boucher; N. Cusack and S. Hourani,
Annals N.Y. Acad. Sci.
603, 172-181 (G. Dubyak and J. Fedan Eds. 1990). For example, UTP may be made in the manner described in Kenner et al.,
J. Chem. Soc.
1954, 2288; or Hall and Khorana,
J. Chem. Soc.
76, 5056 (1954). See Merck Index, Monograph No. 9795 (11th Ed. 1989). UTP&ggr;S may be made in the manner described in R. S. Goody and F. Eckstein,
J. Am. Chem. Soc.
93, 6252 (1971).
For simplicity, Formula I herein illustrates uridine triphosphate active compounds in the naturally occurring D configuration, but the present invention also encompasses compounds in the L configuration, and mixtures of compounds in the D and L configurations, unless specified otherwise. The naturally occurring D configuration is preferred.
The active compounds of Formula (I) may be administered by themselves or in the form of their pharmaceutically acceptable salts, e.g., an alkali metal salt such as sodium or potassium, an alkaline earth metal salt, or an ammonium and tetraalkyl ammonium salt, NX
4
+
(wherein X is a C
1-4
alkyl group). Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
Amiloride (also known as 3,5,-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide), benzamil (also known as 3,5-diamino-6-chloro-N-(benzylaminoaminomethylene) pyrazinecarboxamide) and phenamil (also known as 3,5-diamino-6-chloro-N-(phenylaminoaminomethylene) pyrazinecarboxamide) are known compounds and are disclosed in U.S. Pat. No. 3,313,813 to E. Cragoe. The terms “amiloride,” “benzamil,” and “phenamil,” as used herein (also referred to as “active compounds” herein); include the pharmaceutically acceptable salts thereof, such as (but not limited to) amiloride hydrochloride, benzamil hydrochloride or phenamil hydrochloride. Amiloride, benzamil or phenamil used to prepare compositions for the present invention may alternatively be in the form of a pharmaceutically acceptable free base of amiloride, benzamil or phenamil. Because the free base of the compound is less soluble than the salt, free base compositions are employed to provide more sustained release of benzamil or phenamil to the lungs.
Physiologically acceptable salts (also sometimes referred to as “active compounds” herein) used to carry out the method of the present invention are those that hydrate lung mucus secretions by facilitating the transport of water from lung endothelial cells into the mucus. Physiologically acceptable salts are salts that retain the desired biological activity of hydrating lung mucus secretions and do not impart undesired toxicological effects. Physiologically acceptable salts are typically chloride salts, such as sodium chloride, potassium chloride, choline chloride, and N-methyl-D-glucamine chloride. Sodium chloride is currently preferred. These salts may be provided in the form of a dry respirable powder (discussed below) or as an aqueous solution.
The present invention is concerned primarily with the treatment of human subjects. Subjects may or may not be cystic fibrosis patients. The present invention may also be employed for the treatment of other mammalian subjects, such as dogs and cats, for veterinary purposes.
The active compounds disclosed herein may be administered to the lung(s) of a subject by any suitable means. As used herein, the word “concurrently” means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other)

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