Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-08
2002-04-02
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S492000, C514S550000, C514S552000, C514S557000, C514S558000, C514S866000, C554S077000, C554S085000, C554S088000, C554S213000
Reexamination Certificate
active
06365628
ABSTRACT:
BACKGROUND OF THE INVENTION
Diabetes mellitus and its complications are now considered to be the third leading cause of death in Canada and the United States, trailing only cancer and cardiovascular disease.
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.
It has now been found that these have broader area of applications.
Further, we have now synthesized and characterized novel fatty acid analogous which impose an effect on diabetes.
In feeding experiments with the fatty acid 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.
Further, we have shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin.
Further, the compounds have been proved to have an favourable effect on restenosis, and exhibit good anti-oxidative properties.
DIABETES
Diabetes mellitus and its complications are now considered to be the third leading cause of death in Canada and the United States, trailing only cancer and cardiovascular disease. Although the acute and often lethal symptoms of diabetes can be controlled by insulin therapy, the long-term complications reduce life expectancy by as much as one third. Compared with rates of incidence in nondiabetic normal persons, diabetic patients show rates which are increased 25-fold for blindness, 17-fold for kidney disease, 5-fold for gangrene, and 2-fold for heart disease.
There are 2 major forms of diabetes mellitus. One is type I diabetes, which is also known as insulin-dependent diabetes mellitus (IDDM), and the other is type II diabetes, which is also known as noninsulin-dependent diabetes mellitus (NIDDM). Most patients with IDDM have a common pathological picture: the nearly total disappearance of insulin-producing pancreatic beta cells which results in hyperglycemia.
Considerable evidence has been accumulated showing that most IDDM is the consequence of progressive beta-cell destruction during an asymptomatic period often extending over many years. The prediabetic period can be recognized by the detection of circulating islet-cell autoantibodies and insulin autoantibodies.
There is a need for a compound which would be nontoxic and have no side effects but which would prevent clinical IDDM and NIDDM.
Type I diabetes: severe diabetes mellitus, usually of abrupt onset prior to maturity, characterized by low plasma insulin levels, polydipsia, polyuria, increased appetite, weight loss and episodic ketoacidosis; also referred to as IDDM.
Type II diabetes: an often mild form of diabetes mellitus, often of gradual onset, usually in adults, characterized by normal to high absolute plasma insulin levels which are relatively low in relation to plasma glucose levels; also referred to as NIDDM.
Type I and II diabetes are in accordance with an etiologic classification considered as <<primary>> diabetes respectively.
Secondary diabetes comprises pancreatic, extrapancreatic/endocrine or drug-induced diabetes. Further, some types of diabetes are classified as exceptional forms. These include lipoatrophic, myatonic diabetes, and a type of diabetes caused by disturbance of insulin receptors.
Considering the high prevalence of diabetes in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful for the treatment and prevention of this disease could have a profound beneficial effect on their health. There is a need in the art for a drug that will reduce the concentration of glucose in the blood of diabetic subjects without significant adverse side effects.
It is therefore an object of the present invention to provide a treatment regimen that is useful in lowering the blood glucose and to treat a diabetic condition.
It is yet another object of the invention to provide a treatment regimen that is useful in lowering the concentration of insulin in the blood, and to increase the effect of the remaining insulin.
MECHANISMS OF ACTION
Minor modifications of natural fatty acids, sulphur, selenium or oxygen replacing one or more of 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) is most thoroughly studied and we have shown several beneficial effects in various test animals.
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. It is also shown that the present compounds modifies the fat content, and it is anticipated that the present compounds also will modify the fat distribution.
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 analogous will lower the plasma levels of triglycerides and cholesterol. TTA and TSA are far more potent in this respect than polyunsaturated fatty acids like EPA.
As mentioned above, an important mechanism of action of 3-thia fatty acids is a significant increased mitochondrial fatty acid oxidation reducing the availability of fatty acids for esterification. The synthesis of triacylglycerol and cholesterol is reduced and the secretion of VLDL from the liver is decreased (10). This has the effect of reducing the production of LDL. All these effects seem to be at least partly mediated by peroxisome proliferator activated receptors (PPAR), ubiquitous transcription factors involved in the regulation of lipid metabolism. We have shown that TTA is a potent ligand of PPAR&agr;, a transcription factor regulating the catabolism of fatty acids and eicosanoids, and a less potent ligand of PPAR&ggr;, which is involved in the regulation of adipocyte differentiation.
Obesity is a common feature of non insulin dependent diabetes mellitus (NIDDM) and a risk factor for its development. NIDDM is often linked to hypertension, dyslipidemia, elevated levels of plasma free fatty acids and an increased risk of cardiovascular disease. NIDDM patients are characterised by resistance to insulin action on glucose uptake in peripheral tissues and dysregulated insulin secretion.
We have shown that TTA decrease hyperinsulinemia and markedly improved insulin action on glucose utilisation. TTA did also prevent diet-induced insulin resistance. In contrast to the prior known antidiabetic glitazones TTA did not increase body weight gain.
These effects may at least partly be explained by increased influx of fatty acids and enhanced fatty acid oxidation in the liver. The data thus suggest a role for TTA in both lipid and glucose homeostasis in vivo.
As clearly shown in the experimental section the compounds of the present invention inhibit an increase in the body weight and adipose tissue mass of animals given either a high fat or a high sucrose diet. This make the compounds of the present invention very suitable as pharmaceutical and/or nutritional agents for the treatment of obesity, i.e. the compounds can be used as a slimming agent to provide a body weight or adipose tissue weigh reduction.
Further the compounds of the present invention can be used as an anti-diab
Carr Deborah D.
Reed & Associates
Thia Medica AS
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