Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-08
2002-07-09
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S557000, C514S558000, C514S550000
Reexamination Certificate
active
06417232
ABSTRACT:
The present invention relates to novel fatty acid analogues which can be used for the treatment and/or prevention of primary and secondary stenosis. Further, the present invention relates to the use of said analogues for the treatment of diseases caused by procedural vascular trauma, and more specifically the invention relates to conditions associated with smooth muscle cell proliferation.
Many pathological conditions have been found to be associated with smooth muscle cell proliferation. Such conditions include restenosis, atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, smooth muscle neoplasms such as leiomyoma and leiomyosarcoma of the bowel and uterus and uterine fibroid or fibroma.
Over half a million interventional intravascular procedures are performed each year. While such invasive procedures continue to improve over time, as many as 30-50% of the procedures performed each year fail as a result of restenosis, i.e. the formation of secondary stenosis. The reduction of restenosis is, therefore, often cited as the most critical factor in increasing the success realised in the treatment of cardiovascular disease through the use of interventional intravascular procedures, such as angioplasty, atherectomy, and procedures utilising stents and laser technology.
In balloon angioplasty, e.g. Percutaneous Transluminal Coronary Angioplasty (PTCA), a small incision is made to an artery in the patient's leg or arm and a long hollow tube, called a guide catheter, is inserted into the artery. A thick guide wire and deflated balloon catheter are then inserted into the guide catheter and are carefully advanced through the patient's blood vessels using x-ray visualisation. The deflated balloon is advanced until it reaches the site of the luminal narrowing, at which point the physician inflates the balloon one or more times to a pressure of about 4-6 atm for about 60 sec. When inflated, the balloon cracks and fractures the plaque and stretches the muscle fibre in the artery wall beyond its ability to recoil completely. Although no plaque is removed in this procedure, the fracturing of the plaque and the stretching of the arterial wall increase the vessel lumen, thereby allowing for increased blood flow.
The restenosis that accompanies such procedures is characterised by platelet aggregation and adhesion, smooth muscle cell proliferation, narrowing of the vessel lumen, restricted vasodilatation, and an increase in blood pressure. Smooth muscle cells in the intimal layer of the artery have been reported to enter the growth cycle within about 2-3 days of these procedures and to proliferate for several days thereafter (intimal hyperplasia).
Compounds that reportedly suppress smooth muscle proliferation in vitro may have undesirable pharmacological side effects when used in vivo. Heparin is an example of one such compound, which reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the potential adverse side effect of inhibiting coagulation.
As is apparent from the foregoing, many problems remain to be solved in the use of inhibitory drugs to effectively treat smooth muscle cell mobilisation and proliferation. It would be highly advantageous to develop new compositions or methods for inhibiting stenosis, restenosis or related disorders due to proliferation and mobilisation of vascular smooth muscle cells following, for example, traumatic injury to vessels rendered during vascular surgery.
Treatment with modified fatty acids represent a new way to treat these diseases.
EP 345.038 and PCT/NO95/00195 describes the use of non-&bgr;-oxidizable fatty acid analogues for the treatment of hyperlipidemic conditions.
It has now been found that these fatty acid analogues have broader area of applications.
Further, we have now synthesised and characterised novel fatty acid analogues.
In feeding experiments with the fatty acid analogues of the present invention, the results show that these compounds lower the adipose tissue mass and body weight, and are thus potent drugs for the treatment of obesity and overweight. These results are described and claimed in the Applicants co-pending application PCT/NO99/00135.
We have also shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin. These results are described and claimed in the Applicants co-pending application PCT/NO99/0136.
We have shown that the compounds of the present invention inhibit the formation of secondary stenosis, and the present application thus relates to the use of these compounds for the prevention and/or treatment of restenosis. Further, we have shown that the compounds inhibit the proliferation and mobilisation of smooth muscle cells, and lower the concentration of plasma homocysteine. It is thus anticipated that the compounds also will have a preventive and/or therapeutic effect on primary stenosis. Further, it is anticipated that the present compounds will be useful for the treatment and/or prevention of atherosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke and smooth muscle cell neoplasms, and also diseases caused by procedural vascular trauma.
The novel compounds of the present invention are characterised by minor modifications of the natural fatty acids. Sulphur, selenium or oxygen are preferably substituted for one or more of the carbons in the fatty acid backbone. The compounds defined by the formula I have properties which give them a unique combination of biological effects.
Tetradecylthioacetic acid (TTA) and tetradecylselenioacetic acid (TSA) are most thoroughly studied, and we have shown several beneficial effects in various model animal systems.
The studies have shown that TTA has properties very similar to natural fatty acids, the main difference being that TTA is not oxidised by the mitochondrial &bgr;-oxidation system. However, the presence of compounds of the present invention have been shown to increase the &bgr;-oxidation of other (non-substituted) fatty acids.
Administration of TTA to rats for 12 weeks nearly doubled the hepatic and plasma content of monounsaturated fatty acids (mainly oleic acid), while polyunsaturated fatty acids (mainly linoleic acid and DHA) decreased. Thus the compound of the present invention modifies the composition of the lipids in various tissues.
Feeding moderate doses of TTA to animals like rats, mice, rabbits and dogs decreased both plasma cholesterol and triacylglycerol levels within days of treatment. We have also shown the same effect for TSA, and compounds of the present invention with Sulphur substituted in positions 5 or 7 have been shown to increase the &bgr;-oxidation, and it is thus anticipated that also these fatty acid analogues will lower the plasma levels of triacylglycerols and cholesterol. TTA and TSA are far more potent in this respect than polyunsaturated fatty acids like EPA.
The experimental data of the present invention have unexpectedly revealed that the formation of secondary stenosis (restenosis) after angioplasty is markedly reduced or inhibited in various model animals given the compounds of formula I either orally or locally. This is clearly demonstrated in the experimental section, examples 3 and 4, which demonstrates that the artery diameter, several weeks after the angioplasty procedure, is maintained for animals given TTA, while the diameter is markedly reduced for control animals. These in vivo results clearly demonstrate the potential of these compounds for the prevention of the formation of secondary stenosis.
The action mechanisms for the formation of restenosis after PTCA are not completely understood, but it have been shown that restenotic lesions has an overgrowth of smooth muscle cells in the intimal layers of the vessel.
We have shown that the compounds of the present invention reduce the growth and mobilisation of smooth muscle cells. Increased smooth muscle cell proliferation has also been associated with atherosclerosis, coronary heart disease, thrombosis, myocardial infa
Fay Zohreh
Kwon Brian-Yong
Reed & Associates
Thia Medica AS
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