Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-06-09
2003-12-30
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S061000, C514S062000, C536S018700, C536S021000, C536S123000
Reexamination Certificate
active
06670339
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to sulfated oligosaccharides, and in particular to the use of certain sulfated oligosaccharides as agents for lowering blood levels of triglycerides such as, for example in treatment of hypertriglyceridaemia.
BACKGROUND TO THE INVENTION
It has been proposed that triglycerides may be an independent risk factor for coronary artery disease
1-3
and a major study has shown that elevated triglyceride levels, with elevated total cholesterol/HDL cholesterol in coronary patients are associated with an increased risk of further coronary events
4
. Various forms of hypertriglyceridaernia are associated with varying morbidity
5
and one study has shown that plasma triglyceride concentrations have a high predictive power for coronary arterial disease in women
6-7
.
A number of studies have shown that treatment with heparin, a high molecular weight, N,O-sulfated polysaccharide, affects blood triglyceride levels
8,9
. Other studies have shown that a heparin derivative, Fragmin, also affects blood triglyceride levels
9
. Results from various studies with heparin have been inconsistent with regard to effects on triglycerides. Thus, for example, Schrader et al. found that treatment with unfractionated heparin caused a significant increase in triglyceride levels but Fragmin caused no change in triglyceride levels
10
. Leidig et al. found that acute treatment with heparin invariably caused a decrease in blood levels of triglycerides
8
. Monreal et al., on the other hand, found that chronic treatment with either heparin or Fragmin caused substantial but not statistically significant increases in blood levels of triglycerides
9
.
These variable results are probably due to the immense structural diversity of the glycosaminoglycan heparin. It would be anticipated that sulfated oligosaccharides, which are structurally more homogeneous, would more reproducibly and predictably affect blood triglyceride levels.
A number of agents are used to treat hypertriglyceridaemia and its complications including, inter alia, the fibrates, HMG CoA reductase inhibitors and bile acid-binding resins
11
, although none of these are ideal.
Prior International Patent Application No. PCT/AU96/00238 discloses the preparation of a class of sulfated oligosaccharides based on polymers of monosaccharide units linked by 1→2, 1→3, 1→4 and/or 1→6 glycosidic bonds and consisting of from 3 to 8 monosaccharide units, which are potent inhibitors of mammalian heparanases, and can be used to inhibit human angiogenesis, tumour metastasis and inflammation.
In work leading to the present invention, it has been shown that these sulfated oligosaccharides may also be used to lower blood levels of triglycerides.
SUMMARY OF THE INVENTION
In accordance with one aspect, the present invention provides a method of lowering blood triglyceride levels in a human or other warm blooded animal which method comprises administering to said animal an effective amount of a sulfated oligosaccharide of Formula (I):
R
1
—(R
x
)
n
—R
2
(I)
wherein each of R
1
, R
2
and R
x
is a monosaccharide unit which may be the same or different and wherein the monosacharide units are linked by 1→2, 1→3, 1→4 and/or 1→6 glycosidic bonds; and
n is an integer from 1 to 6.
Preferably, the sulfated oligosaccharides has Formula (II):
Rx—(Rx)
n
—Rx (II)
wherein Rx represents the same monosaccharide unit with adjacent monosaccharide units being linked by 1→2, 1→3, 1→4 and/or 1→6 glycosidic bonds, and n is an integer of from 1 to 5 and preferably 3 or 4.
As used herein, terms such as “lowering of blood levels of triglycerides” or “lowering of circulating triglyceride levels” are intended to encompass both prophylactic and therapeutic treatment of a patient in need of such treatment.
REFERENCES:
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patent: 5739115 (1998-04-01), Fugedi
patent: 5783568 (1998-07-01), Schlessinger
patent: A-10397/83 (1983-07-01), None
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patent: A-12127/92 (1992-09-01), None
patent: A-60524/94 (1994-10-01), None
patent: A2 0208623 (1987-01-01), None
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Angela Horne and Peter Gettins, H NMR Spectroscopic Studies On The Interactions Between Human Plasma Antithrombin III and Defined Low Molecular Weight Heparin Fragments, Biochemistry, Feb. 11, 1992, vol. 34, No. 5, pp. 2286-2294.
Maurice Petitou, Jean-Claude and Jean Choay, European Journal of Biochemistry, Febs, 1998, vol. 176, pp. 637-640.
P.V.G. Menon and P.A. Kurup, Nature Of The Dietary Carbohydrate and Metabolism Of Glycosaminoglycans and Glycoproteins In Rats, Department Of Biochemistry, University of Kerala, Jul. 30, 1975, pp. 555-562.
Susan P. Williams and Edward A. Johnson, Release Of Lipoprotein Lipase And Hepatic Triglyceride Lipase In Rats By Heparin And Other Sulphated Polysaccharides, Thrombosis Research, 1989, vol. 55, pp. 361-368.
K. Saraswathi Devi and P.A. Kurup, Hypolipidaemic Activity Of Phaseolus Mungo (Blackgram) In Rats Fed A High-Fat-High-Cholesterol Diet, Atherosclerosis, 1972, vol. 15, pp. 223-230.
K. Saraswathi Devi and P.A. Kurup, Hypolipidaemic Activity Of The Protein And Polysaccharide Fraction From Phaseolus Mungo (Blackgram) In Rats Fed A High-Fat-High-Cholesterol Diet, Atherosclerosis, 1973, vol. 18, pp. 389-397.
B. Oswald, F. Shelburne, B. Landis, A. Linker, and S. Quarfordt, The Relevance of A Glycosaminoglycan Sulfates To APO E Induced Lipid Uptake By Hepatocyte Monolayers, Biochemical And Biophysical Research Communications, Nov. 26, 1980, vol. 141, No. 1, 1986, pp. 158-164.
Leidig, G. et al “Effects of heparing and cardiac catheterization on serum lipoprotein and triglyceride level” Am. J. Cardiol., vol 74, pp. 47-52, 1994.*
Monreal, M. et al “Effects of long-term therapy with either heparin or low-molecular weight heparin on serum lipid levels” Haemostasis, vol 25, pp. 283-287, 1995.
Cowden William B.
Parish Christopher R.
Fulwider Patton Lee & Utecht LLP
Maier Leigh C.
The Australian National University
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