Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-04-19
2001-08-28
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S210030
Reexamination Certificate
active
06281199
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of heart disease, more particularly to the use of certain antibiotics in combatting atheroscelorsis.
DESCRIPTION OF THE PRIOR ART
Coronary heart disease is the largest single cause of premature death in the western world, and in the UK alone is responsible for about 160,000 deaths annually. The traditional view held by a significant proportion of the medical profession is that age and social and economic factors are the predominant causes of heart disease. In recent years, however, there has been a significant number of reports implicating certain bacteria in coronary heart disease, although these have met with considerable scepticism in some quarters.
Bacteria referred in such reports include
Helicobacter pylori
and
Chlamydia pneumoniae
. Thus, for example. Finnish researchers in the late 1980s reported that coronary heart disease sufferers were more likely to have high levels of antibodies to the
Chlamydia pneumoniae
bacterium than healthy people (The Lancet, 1988: 983-986). More recently, the organism itself has been found in atherosclerotic arteries of patients undergoing abdominal aortic aneurysm repair (J. Clin. Pathol., 1996, 49(2): 102-106). In the Journal of the American College of Cardiology, June 1996, 27(7): 1555-61, it was reported that 79% of patients undergoing surgery to excise atherosclerotic plaques showed an antibody to
Chlamydia pneumoniae
active in the lesions, but that only 4% of non-atherosclerotic pathology specimens showed the same antibody. It was alleged on this basis that the bacterium may be specifically linked with atheroma and not with other causes of arterial damage.
Other workers have reported similar findings, and it has been suggested that inflammation associated with persistent bacterial infection of arterial walls could trigger an immune reaction which raises fibrinogen and tissue factor levels in the blood and increases the potential for atherothrombosis.
However, there is still considerable scepticism about this theory within the medical profession, particularly amongst cardiologists, and many workers doubt whether
Chlamydia pneumoniae
is present in the diseased heart at all or, if it is, it is merely there as an innocent bystander. Thus, in the Journal of Infectious Diseases, 1996, 173(4): 957-62 it was reported that a research team had failed to culture
Chlamydia pneumoniae
from 58 samples of atheroma. Opinions are therefore firmly divided on the role, if any, of
Chlamydia pneumoniae
in heart disease.
The present invention is based on the unexpected finding that administration of certain antibiotics, more specifically macrolide antibiotics such as azithromycin, may lead to a reduction in markers of blood clotting and inflammation in the blood of post-myocardial infarction patients, possibly through eradication of underlying
Chlamydia pneumoniae
infection. Such administration of macrolide antibiotics may therefore be beneficial not only to cardiac patients, for example by reducing inflammation of heart tissue, blood clotting, susceptibility to angina, the likelihood of readmissions and/or need for bypass or other surgery, but also prophylatically to patients in general.
SUMMARY OF THE INVENTION
Thus viewed from one aspect the present invention provides a method of combatting atherosclerosis, said method comprising administering an effective amount of a macrolide antibiotic, for example an azalide, optionally together with one or more pharmaceutically acceptable carriers or excipients, to a subject.
In the method according to the invention, the macrolide antibiotic may if desired be administered with other useful agents such as platelet aggregation inhibitors, blood thinning agents, and/or lipid lowering agents. Thus in a further aspect, the present invention provides a composition for combatting atherosclerosis, the composition comprising a macrolide antibiotic or a derivative thereof, e.g. azithromycin together with one or more of the agents selected from the group consisting of platelet aggregation inhibitors, blood thinners, and/or lipid-lowering agents etc, optionally together with one or more carriers or excipients.
Viewed from a further aspect the present invention provides the use of a macrolide antibiotic e.g. azithromycin or a derivative thereof for the preparation of a composition for use in combatting atherosclerosis.
As is well known, macrolide antibiotics are characterised by the presence of a macrocyclic lactone ring to which one or more sugar molecules are attached. Representative examples of such antibiotics include erythromycin, spiramycin, oleandomycin, clarithromycin, dirithromycin, roxithromycin, josamycin, kitasamycin, midecamycin, miocamycin, rokitamycin, rosaramicin, azithromycin and derivatives thereof, e.g. salts such as phosphates and esters such as acetates.
Azithromycin [(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-(2,6-Dideoxy-3-C-3-O-dimethyl-&agr;-L-ribohexopyranosyloxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8, 10,12,14-heptamethyl-11-(3,4,6-trideoxy-3-dimethylamino-&bgr;-D-xylohexopyranosyloxy)-1-oxa-6-azacyclopentadecan-15-one], available commercially in the dihydrate form as Zithromycin®, is a preferred macrolide or azalide antibiotic for use in accordance with the invention, having proved effective using single daily dosages over periods as short as three days. It will be appreciated that such simple dosage regimens are highly advantageous in securing patient compliance.
A typically daily dose of a macrolide antibiotic such as azithromycin will be 500 mg given orally, for example for up to 3 days, although other dosages and methods of administration may if desired by employed. It may be advantageous to administer a second course of the antibiotics some time, e.g. one, two or three months, after the first course in order to maximise the effect of the treatment. It may be even more advantageous to administer further courses of the antibiotic at intervals of one, two or three months after the second course in order to sustain the benefit. Typically this may be carried out for up to a year after the initial course has been administered.
The invention will now be described in a non-limiting manner by way of example:
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Proc. Natl. Acad. Sci. USA; Kuo et al;Chlamydia pneumoniae(TWAR) in coronary arteries in young adults (15-34 years old); 1995; 92:6911-6914.
The Journal of Infectious Diseases; Weiss et al; Failure to detectchlamydia penumoniaein coronary atheromas of patients undergoing atherectomy; 1996; 173:957-62.
JACC; Muhlenstein et al; Increased incidence of chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease; 1996; 27(7):1555-61.
The Lancet; Saikku et al; Serological evidence of an association of a novel chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction; 1988; 983-985.
Transplantation Proceedings; Virella et al; Infections and atherosclerosis; 1987; vol. XIX, No. 4, Suppl 5:26-35.
Journal of Infection; Bromage et al; Embolic phenomena in chlamydial infection; 1980; 2:151-159.
Clinical Immunology and Immunopathology; Lopes-Virella et al; 1985; 37:377-386.
Heart; Niemelä et al; Couldhelicobacter pyloriinfection increase the risk of coronary heart disease by modifying serum lipid concentrations?; 1996; 75:573-575.
J. Clin. Lab. Immunol; Smith et al; Circulating immune complexes in myocardial infarction; 1983; 12:197-199.
The New England Journal of Medicine; Grayston et al; 1986; vol. 315, No. 3:161-168.
Immunology Letters; Cristea et al; Characterization of circulating immune complexes in heart disease; 1986; 13:45-49.
Atherosclerosis; Füst et al; Studies on the occurrence of circulating immune complexes in vascular diseases; 1978; 29:181-190.
Scan
Bacon & Thomas
Jagoe Donna
Krass Frederick
Pfizer Inc.
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