Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2001-04-19
2002-09-10
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S464000, C424S468000, C424S474000, C424S475000, C424S479000, C424S481000, C424S489000, C424S490000, C424S493000, C424S496000
Reexamination Certificate
active
06447797
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to phosphoinositides which have demonstrated antibacterial activity and particularly to phosphoinositides which can be used for the prophylaxis and treatment of bacterial infections and particularly for the prophylaxis and treatment of bacterial infections caused by
Haemophilus influenzae.
BACKGROUND OF THE INVENTION
In the United States, otitis media, next to upper respiratory tract infections, is the most common cause for outpatient visits to pediatricians. Fifteen to twenty per cent of children younger than six years of age contract otitis media. Otitis media is an inflammation of the middle ear characterized by symptoms such as otalgia, hearing loss and fever. One of the primary causes of these symptoms is a build up of fluid (effusion) in the middle ear. Complications include permanent hearing loss, perforation of the tympanic membrane, acquired cholesteatoma, mastoiditis, and adhesive otitis. Children who develop otitis media in the first years of life are at risk for recurrent acute or chronic disease.
One of the primary causes of otitis media is
Haemophilus influenzae,
which is commonly known as
“H. influenzae.
” It is thought that
H. influenzae
causes otitis media by adhering to nasopharyngeal cells. The adherence of
H. influenzae
to nasopharyngeal cells causes those cells to become infected and to produce secretions. The middle ear becomes infected because mechanical or functional obstruction of the Eustachian tube, which protects the middle ear from nasopharyngeal secretions, results in negative middle ear pressure. This negative pressure causes the nasopharyngeal secretions to enter the middle ear resulting in an infection, such as otitis media, usually with effusion.
Typically, otitis media is treated by means of administering a course of antibiotics consisting of a penicillin derivative. Other supportive therapies, such as analgesics, antipyretics and local heat are also helpful. Often, surgery is required to remove fluid from the middle ear and to relieve the pain experienced by the child.
Currently, no reliable prophylactic treatments are known. It has been demonstrated that human casein inhibits the adhesion of
H. influenzae
to human respiratory tract epithelial cells. See Aniansson, et. al.,
Microbial Pathogenesis
1990;8:315-323. Aniansson, et al., found that human casein represents a new mechanism for the protection by breast-milk against respiratory tract infection. Thus, it is thought that human casein may be effective as a prophylactic treatment for otitis media but further study is required.
Polyphosphoinositides have been reported to be present in inner ear and kidney tissue. See U.S. Pat. No. 4,897,384 to Janoff, et al. Phosphatidylinositol diphosphate has been postulated to serve as an in vivo receptor for aminoglycoside antibiotics. See Lodhi, et al., Biochem. Pharmacol. 29:597-601 (1990). Dipalmitoylphosphatidylinositol-3,4-diphosphate ammonium salt (PI-3,4-PP) is known to be a membrane lipid present in human erthyrocytes. However, no anti-bacterial activity of polyphosphoinositides has been previously reported.
For these reasons, a need still exists in the art for a composition and method for the prophylaxis and treatment of infections caused by
Haemophilus influenzae
and its clinical manifestations, such as, for example, otitis media.
SUMMARY OF THE INVENTION
It has been discovered that certain phosphoinositides demonstrate antibacterial activity. Particularly, these phosphoinositides have been discovered to prevent the adhesion of
H. influenzae
onto the nasopharyngeal cells of mammals, and, in particular, humans. Phosphoinositides useful with the present invention have the following formula (1):
wherein R
1
and R
2
are selected from the group consisting of hydrogen and monounsaturated and saturated fatty acids having a carbon chain length of C
6
to C
20
and R
2
and R
1
can be the same or different; and R
3
to R
7
are selected from the group consisting of hydrogen or a phosphate moiety with at least two of R
3
to R
7
being a phosphate moiety; and hydrates and pharmaceutically acceptable salts thereof.
One aspect of the present invention is directed to a nutritional formulation for the prophylaxis and treatment of
Haemophilus influenzae
infection and its clinical manifestations comprising an effective amount of a compound of the formula (1). Another aspect of the present invention is directed to a pharmaceutical composition for the prophylaxis and treatment of
Haemophilus influenzae
infection and its clinical manifestations comprising an effective amount of a compound of the formula (1). Still another aspect of the present invention is directed to a method for the prophylaxis and treatment of bacterial infections comprising administering to a patient an effective amount of a compound of the formula (1). Yet another aspect of the present invention is directed to a method for the prophylaxis and treatment of otitis media comprising administering to a patient an effective amount of a compound of the formula (1).
In the above aspects of the invention, R
1
and R
2
are desirably both fatty acids; R
1
is desirably a fatty acid and R
2
is desirably hydrogen; or R
1
and R
2
are both desirably hydrogen.
If R
1
and R
2
are both fatty acids, then R
3
, R
6
and R
7
are desirably hydrogen and at least one of R
4
and R
5
is desirably a phosphate moiety. More desirably, the compound is selected from the group consisting of diacylphosphatidylinositol-3-monophosphate, diacylphosphatidylinositol4-monophosphate and diacylphosphatidylinositol-3,4-diphosphate. Most desirably, the compound is dipalmitoylphosphatidylinositol-3,4-diphosphate.
If R
1
is a fatty acid and R
2
is hydrogen, then R
3
, R
6
and R
7
are desirably hydrogen and at least one of R
4
and R
5
is desirably a phosphate moiety. More desirably, the compound is selected from the group consisting 1-monoacylphosphatidylinositol-3-monophosphate, 1-monoacylphosphatidylinositol-4-monophosphate and 1-monoacylphosphatidylinositol-3,4-diphosphate.
If R
1
and R
2
are both hydrogen, then R
3
, R
6
and R
7
are desirably hydrogen and at least one of R
4
and R
5
is desirably a phosphate moiety. More desirably, the compound is selected from the group consisting of 3-phosphoglyceroinositol-3-monophosphate, 3-phosphoglyceroinositol4-monophosphate and 3-phosphoglyceroinositol-3,4-diphosphate.
Other objects and advantages of the invention will be apparent from the following detailed description and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
As stated above, it has been discovered that certain phosphoinositides demonstrate antibacterial activity. Particularly, these phosphoinositides have been discovered to prevent the adhesion of
H. influenzae
onto the nasopharyngeal cells of mammals, and, in particular, humans. Phosphoinositides useful with the present invention have the following formula (1):
wherein R
1
and R
2
are selected from the group consisting of hydrogen and monounsaturated and saturated fatty acids having a carbon chain length of C
6
to C
20
and R
3
and R
2
can be the same or different; and R
3
to R
7
are selected from the group consisting of hydrogen or a phosphate moiety with at least two of R
3
to R
7
being a phosphate moiety; and hydrates and pharmaceutically acceptable salts thereof.
In the above compound, R
1
and R
2
are desirably both fatty acids; R
1
is desirably a fatty acid and R
2
is desirably hydrogen; or R
1
and R
2
are both desirably hydrogen.
If R
1 and R
2
are both fatty acids, then R
3
, R
6
and R
7
are desirably hydrogen and at least one of R
4
and R
5
is desirably a phosphate moiety. More desirably, the compound is selected from the group consisting of diacylphosphatidylinositol-3-monophosphate, diacylphosphatidylinositol-4-monophosphate and diacylphosphatidylinositol-3,4-diphosphate. Most desirably, the compound is dipalmitoylphosphatidylinositol-3,4-diphosphate.
If R
1
is a fatty acid and R
2
is hydrogen, then R
3
, R
6
and R
7
are desirably
Anderson Steven Neal
Huang Yung-Sheng
Hwang Shie-Ming
Liu Jim-Wen
Meulbroek Jonathan A.
Abbott Laboratories
Dixon J. Michael
Spear James M.
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