Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-09
2003-10-28
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S061000, C536S122000, C536S123000, C536S123100
Reexamination Certificate
active
06638916
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to sulfated oligosaccharides, and in particular to the use of certain sulfated oligosaccharides as inhibitors of vascular smooth muscle cell hyperplasia, particularly in the treatment of atherosclerosis and restenosis after coronary angioplasty.
BACKGROUND OF THE INVENTION
The normal artery wall consists of luminal surface covered by a unicellular layer of endothelial cells and a subluminal multicellular layer of smooth muscle cells embedded in a complex extracellular matrix (ECM). A major component of the ECM is the glycosaminoglycan, heparan sulfate, which is believed to normally inhibit smooth muscle cell proliferation
1-3
. In contrast, atherogenesis is associated with a loss of ECM heparan sulfate with a consequent migration and proliferation of smooth muscle cells
1-3
. The factors which initiate ECM degradation are poorly understood, although it has been suggested that heparanase produced by leukocytes infiltrating the developing atherosclerotic plaque may result in the loss of ECM heparan sulfate
4
.
The treatment of narrow and occluded coronary arteries in atherosclerosis frequently involves dilatation by balloon angioplasty. Unfortunately, in approximately 30% to 40% of patients restenosis occurs due to vascular hyperplasia, a process which is believed to result from the denudation of vessel endothelium and the subsequent migration and proliferation of subendothelial smooth muscle cells
5
. As with atherogenesis, heparanase-mediated loss of ECM heparan sulfate is believed to be a critical factor in angioplasty-associated restenosis
1-2
.
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 inhibit the vascular smooth muscle cell hyperplasia associated with angioplasty-associated restenosis and atherosclerosis.
SUMMARY OF THE INVENTION
In accordance with one aspect, the present invention provides a method for the inhibition of vascular smooth muscle cell hyperplasia, and particularly for the treatment of atherosclerosis or angioplasty-associated restenosis, in a human or other warm blooded animal patient in need of such treatment, which comprises administration to the patient of an effective amount of at least one sulfated oligosaccharide, wherein the oligosaccharide has the general formula I:
R
1
—(R
x
)
n
—R
2
(I)
wherein R
1
and R
2
and each R
x
represents a monosaccharide unit, all of which may be the same or different, 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 6, preferably 3 or 4.
Preferably, the sulfated oligosaccharides have the general formula II:
Rx—(Rx)
n
—Rx (II)
wherein Rx represents the same monosaccharide unit, 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, preferably 3 or 4.
As used herein, the terms “inhibition of vascular smooth muscle cell hyperplasia” and “treatment of atherosclerosis or angioplasty-associated restenosis” are intended to encompass both prophylactic and therapeutic treatment of a patient in need of such treatment.
As well as being potent heparanase inhibitors, a further advantage of the sulfated oligosaccharides described above is that they have two additional effects. First, they are effective inhibitors of angiogenesis, probably by interfering with the action of heparan sulfate-binding growth factors (disclosed in prior International Patent Application No. PCT/AU96/00238) and, second, they possess unique anticoagulant/antithrombotic activity (disclosed in prior International Patent Application No. PCT/AU98/00151). Since angiogenesis is an important feature of coronary atherosclerotic plaque formation
6
and intravascular thrombus formation is a major risk factor associated with angioplasty and atherosclerosis
7
, these two additional activities of the sulfated oligosaccharides further enhance their therapeutic potential.
DETAILED DESCRIPTION OF THE INVENTION
The sulfated oligosaccharides which are used in accordance with this invention are based on polymers of monosaccharide units, which may be linked by 1→2, 1→3, 1→4 and/or 1→6 glycosidic bonds and which may consist of from 3 to 8 monosaccharide units. Preferably, the oligosaccharides consist of from 3 to 6 monosaccharide units (that is n is from 1 to 4), more preferably from 5 to 6 monosaccharide units (n is from 3 to 4). The polymers may comprise homopolymers containing only one type of monosaccharide unit, or heteropolymers containing two or more different types of monosaccharide units, although homopolymers are preferred.
The monosaccharide units which are linked together to form the oligosaccharides are preferably hexoses, such as mannose, altrose, allose, talose, galactose, idose, or gulose. Particularly preferred hexoses are mannose and galactose. The hexoses may be in either the D- or the L-configuration.
The oligosaccharides of general formulae I and II also include compounds wherein the monosaccharide units are derivatised, in particular where the units are phosphate, acetyl or other ester derivatives of monosaccharides.
In general, the sulfated oligosaccharides of this invention may be prepared by sulfation of oligosaccharides by methods known per se in the art to give their corresponding O-sulfated derivatives. Suitable sulfation methods are described in International Patent Application No. PCT/AU96/00238, the contents of which are incorporated by reference. The oligosaccharides to be sulfated may be naturally occurring products including oligosaccharides occurring naturally as well as oligosaccharides prepared by enzymatic or chemical degradation of naturally occurring polysaccharides (such as mannan and a phosphomannan exopolysaccharide from the yeast
Pichia holstii
). Alternatively, the oligosaccharides may be prepared synthetically by the process disclosed in International Patent Application No. PCT/AU96/00238.
The present invention extends to the use of at least one sulfated oligosaccharide as described above in inhibition of vascular smooth muscle cell hyperplasia, and particularly in treatment of atherosclerosis on angioplasty-associated restenosis, in a human or other warm-blooded animal patient in need of such treatment.
The invention also extends to the use of at least one sulfated oligosaccharide as described above in the manufacture of a medicament for the inhibition of vascular smooth muscle cell hyperplasia, and particularly for the treatment of atherosclerosis or angioplasty-associated restenosis, in a human or other warm-blooded animal patient.
Furthermore, this invention also provides a pharmaceutical or veterinary composition for inhibition of vascular smooth muscle cell hyperplasia and particularly for treatment of atherosclerosis or angioplasty-associated restenosis, which comprises at least one sulfated oligosaccharide as described above, together with a pharmaceutically and veterinarily acceptable carrier or diluent therefor.
The active component is administered in therapeutically effective amounts. A therapeutically effective amount means that amount necessary at least partly to attain the desired effect, or to delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the particular condition being treated. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters including age, physical condition, size, weight and concurrent treatment. These factors are w
Cowden William B.
Francis Douglas J.
Parish Christopher R.
Fulwider Patton Lee & Utecht LLP
Maier Leigh C.
The Australian National University
Wilson James O.
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