Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Bacteria or actinomycetales
Reexamination Certificate
2000-02-07
2001-04-10
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Bacteria or actinomycetales
C435S252900, C435S853000, C435S856000, C435S857000
Reexamination Certificate
active
06214336
ABSTRACT:
The present invention refers to the use of strains of Lactobacillus being able to reduce the fibrinogen level, and optionally also the cholesterol level, in blood.
BACKGROUND OF THE INVENTION
Fibrinogen is a plasma protein, synthesized in the liver, which in the final step of the blood coagulation cascade by activated thrombin is converted into insoluble fibrin. Fibrin in turn, is in the fibrinolysis reaction decomposed by plasmin, also referred to as fibrinolysin, the normal mechanism for the removal of small fibrin clots from the circulation.
The plasma fibrinogen concentration increases gradually during normal aging from an average of 2.3 mg/ml at 20 years to 3.5 mg/ml at 70 years of age. The increase is coupled with about a 20% decrease in endogenous fibrinolytic activity over the same period. Under conditions of stress or trauma the blood fibrinogen level may double or triple within 48 hours. It has been confirmed that blood fibrinogen is a major determinant of blood and plasma viscosity in the microcirculation, of red cell and platelet aggregation and in the growth of atheromatous lesions. Blood fibrinogen levels are increased and the endogenous fibrinolytic activity decreased by conditions or factors which raise plasma free fatty acid, FFA, levels, see Pickart, L., in Pharmacology 23: 271-280, 1981.
An increased level of fibrinogen is associated with an increased erythrocyte sedimentation rate, which in turn since long has been correlated to a risk for ischemic heart diseases. In acute myocardial infarction the level of plasma fibrinogen as well as the level of free fatty acids are increased.
Fibrinogen as a cardiovascular risk factor is described by Ernst, E., et al., Annals of Internal Medicine 118: 956-963, 1993. In six prospective epidemiologic studies the correlation of fibrinogen levels on the subsequent incidence of myocardial infarction, stroke and peripheral arterial occlusive disease was assessed and the causality of the association was analysed. All prospective studies showed that fibrinogen was associated with subsequent myocardial infarction or stroke. It was concluded that fibrinogen is pathophysiologically related to cardiovascular events and can be considered a major cardiovascular risk factor.
There are several determinants of the fibrinogen level in health and disease, some of which can not be affected such as age, sex and heritage. Others which are amenable to change are lifestyle determinants such as smoking, sedentary life, diet and stress.
An increased cholesterol level, as well as an increased blood pressure are other important risk factors for heart diseases. Serum cholesterol levels generally refer to a combination of HDL, high density lipoproteins, and LDL, low density lipoproteins. Increased levels of LDL cholesterol may be associated with the pathogenesis of atherosclerosis while higher levels of HDL cholesterol appear to lower the risk of heart disease.
PRIOR ART
There are a wide variety of antilipidemic agents which in addition to a prolonged reduction in plasma FFA levels also reduce blood fibrinogen concentrations while enhancing fibrinolytic activity apparently by decreaseing hepatic synthesis of fibrinogen and antifibrinolysins, see Pickart, L., Pharmacology 23(5), 271-80, 1981. As examples of these agents, which are biochemically and structurally diverse, can be mentioned allylpropyl disulfide, the active principle from garlic and onion, acetylsalicylic acid and clofibrate, a fatty acid analogue. Most of these agents have annoying or serious side effects and more efficacious agents should be aimed at.
There are conflicting data regarding the potential hypo-cholesterolemic effect of fermented dairy products in man, and whether intake of these products has any significance in the prevention of coronary heart disease. Gilliland, S. E., et al., Applied and Environmental Microbiology, 49(2): 377-381, 1985, have found that some strains of Lactobacillus acidophilus, but not other, act directly on cholesterol in the gastrointestinal tract and may thus be beneficial in reducing serum cholesterol levels, and by this to lower the incidence of coronary heart disease. It is also reported that certain of said strains have the ability to deconjugate bile salts. In this study pigs were used as an animal model.
There is today no substance known that lowers the fibrinogen levels in patients at risk, safely and selectively.
REFERENCES:
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patent: 5707854 (1998-01-01), Saito et al.
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Bukowska et al. Atherosclerosis, 137(2): 437-8. Decrease in fibrinogen and LDL-cholesterol levels upon supplementation of diet with Lactobacillus plantarum in subjects with moderately elevated cholesterol, Apr. 1998.*
Bjornsson et al. Clinical Pharmacology and Therapeutics, 51(2), 193. Aspirin acetylates fibrinogen and has fibrinolytic effect in man, Mar. 1992.*
H. Bukowska, et al., Dialog Information Service, File 155, Dialog Accession No. 09595669, Medline Accession No. 98283630, 1 page, “Decrease in Fibrinogen and LDL-Cholesterol Levels Upon Supplementation of Diet with Lactobacillus Plantarum in Subjects with Moderately Elevated Cholesterol Letter”, Apr. 1998.
H.J. Oakey, et al., Journal of Applied Bacteriology, vol. 78, No. 2, Dialog Information Service, File 5, Dialog Accession No. 115411251, Biosis Accession No. 98141251, 1 page, “Enzyme Production of Lactobacilli and the Potential Link with Infecti VE Endocarditis”, 1995.
Derwent Abstracts, AN 96-421913, JP 8-208512, Aug. 13, 1996.
So-Young Park, et al., Chemical Abstracts, vol. 125, No. 15, Abstract No. 125:194329, “Effect of Various Lactic Acid Bacteria on the Serum Cholesterol Levels in Rats and Resistance to Acid, Bile and Antibiotics”, Sept. 7, 1996.
Bukowska Hanna
Johansson Marie-Louise
Naruszewicz Marek
Flood Michele C.
Lankford , Jr. Leon B.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Probi AB
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