Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from artemisia
Reexamination Certificate
2000-02-23
2002-03-26
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from artemisia
C424S725000, C424S764000, C424S776000, C424S401000, C424S486000, C424S484000, C514S886000, C514S887000, C514S899000
Reexamination Certificate
active
06361806
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to compositions and methods for treating conditions by topical administration of agents effecting changes in subcutaneous adipose tissue, and specifically to compositions and methods for ameliorating symptoms of disease and treating physical cosmetic conditions.
BACKGROUND OF THE INVENTION
Demographics of population aging has focused special attention on pre- and post-menopausal diseases and breast cancer. About 60% of women reportedly develop palpable cysts by age 40 to 50. While retrospective studies have suggested possible relationships between fibrocystic breast disease, benign breast pain, cyclic mastalgia, benign cysts and increased risk of breast cancer, unfortunately, obvious treatment options have not been forthcoming. In younger women, fibrocystic disease is a common under-diagnosed problem with reported prevalence ranging in different studies from 41% to 69% (1-3; Citations follow the EXAMPLES section, below). It is not clear at present whether microcysts are a normal part of the breast involution process (4) and no specific United States standards of treatment exist (at present) for these conditions. With an unknown etiology, hormone therapy (5,6), caffeine restriction (7) and diet (8-11) have all been suggested as possible treatment options.
In other tissues, age related changes have also been observed. Histologic changes in cutaneous tissues accompanying aging have been evaluated at a cellular level in vitro, with a variety of findings. For example, changes have been observed in extracellular matrix components, (e.g., breakdown and UV damage to collagen fibers and elastin filaments), capillary endothelium (e.g., telangiectasia), loss of elasticity in smooth muscle fibers and changes in cholesterol, triglyceride and fatty acid metabolism.
Unlike plants, animal tissues have a limited ability to desaturate fatty acids, necessitating the intake of essential unsaturated fatty acids. Metabolism of essential fatty acids produces eicosanoids (C
20
fatty acids) including the inflammatory mediators known as prostaglandins, thromboxanes and leukotrienes. On a cellular level, membrane composition and content of unsaturated fatty acids are thought to influence membrane fluidity. Physiologically, high plasma ratios of poly-unsaturated fatty acids to saturated have been associated with lowering of cholesterol and lowering of risk of coronary heart disease and stroke. Dietary control of eicosanoid synthesis has been suggested as a means of disease intervention. Unfortunately, fatty acid metabolism is affected by variable dietary absorption rates, levels of certain hormones, (e.g, insulin, glucagon and steroid hormones), lipoproteins, triglycerides and chylomicrons, as well as tissue stores of fatty acids. These multiple factors make stable dietary control difficult to achieve. Many biologically important fatty acid mediators are also highly labile and not easily administered. Under physiologic conditions, such mediators are generated locally within tissues where they normally act to produce their effects.
Linoleic acid (C
18:2
) is an essential fatty acid having two double bonds, i.e., C
9
═C
10
and C
12
═C
13
(as carbon atoms are numbered from the carboxyl terminus of the fatty acid). &agr;-Linolenic acid (C
18:3
) is an essential fatty acid having three double bonds, i.e., C
9
═C
10
, C
12
═C
13
and C
14
═C
15
as numbered from the carboxyl terminal. Linoleic, &agr;-linolenic and arachidonic acids are the only fatty acids known to be nutritionally essential. In many animal species linoleic acid can be converted in endoplasmic reticulum (microsomes) through &ggr;-linolenic acid (C
6
═C
7
, C
9
═C
10
, C
12
═C
13
; GLA) and dihomo-&ggr;-linolenic acid (C
8
═C
9
, C
11
═C
12
, C
14
═C
15
) into arachidonic acid (i.e., C
20:4
; C
5
═C
6
, C
8
═C
9
, C
11
═C
12
, C
14
═C
15
). Because of the energy dependent requirements (i.e., for NADH and NADPH), the latter process is sensitive to fasting, e.g., extreme dieting, but also malnutrition such as may occur as a result of intravenous feeding, kidney dialysis, liver cirrhosis, endotoxemia and cachesia and chemotherapy in cancer patients. Radiation therapy can also induce membranous fatty necrosis in breast tissues with resultant recurrent lumps (15).
Maternal milk contains linoleic acid and infant formula milks commonly contain essential fatty acids, including linoleic, to prevent cerebral cortical deficiency. Patients with nutritional deficiency in essential fatty acids manifest symptoms of scaly skin that is responsive to oral feeding of linoleate. Linolenic acid and evening primrose oil (rich in gamma-linolenic acid) have been evaluated for possible beneficial skin effects in hemodialysis patients with skin symptoms (13). Levels of linoleic acid can influence insulin responsiveness of vascular smooth muscle cells, and feeding a diet high in linoleic acid to Dahl sensitive hypertensive rats reportedly potentiated hypertension (12).
Nutritionally derived plasma fatty acids are known to control the rate of hepatic lipogenesis in mammals. Lipogenesis involves conversion of glucose, pyruvate and lactate to acyl-CoA intermediates and, after undergoing sequential chain elongation reactions in the endoplasmic reticulum, fatty acids are formed. Carbohydrate, glucose and insulin levels all influence fatty acid metabolism, but conversely, recent studies in rats have suggested that dietary omega-3 fatty acids (i.e., &agr;-linolenic acid) can influence insulin binding and insulin-stimulated glucose transport and lipogenesis in muscle and adipocytes (14).
Arachidonic acid metabolites have a variety of hormone-like effects in tissues and also mediate important protective inflammatory activities: i.e., certain thromboxanes have vasoconstrictor and platelet activating activity; certain prostacyclins are vasodilators; Prostaglandin E2 enhances vascular permeability, is pyrogenic, enhances pain, and can exert immunosuppressive effects on mast cells (involved in allergy) and lymphocytes and macrophages (involved in immune defense). Dietary linoleic acid, but not gamma-linolenic acid reportedly improved aggregation responses of platelets collected from patients with liver cirrhosis (16). Novel diets low in linoleic acid and containing eicosapentaenoic acid (EPA) and gamma-linolenic acid have been considered for enteral use to reduce endotoxemia (17).
Adipocytes are a major site of fatty acid metabolism, lipogenesis, and production of lipid mediators that exert effects on surrounding tissues. Adipocytes store fatty acids in special intracellular fat vacuoles. Adipocytes are also reported to provide a stored source of estrogen in breast tissues with levels of intracellular estrogen changing during the menstral cycle and in menopause (18). Certain studies suggest a major role for adipose tissue in post-menopausal aromatase P450 catalyzed conversion of C
19
steroids to estrogens (19) and in breast tissues of women with breast cancer (20, 21). Stromal-epithelial cell interactions in breast cancer are recently reviewed (22). Growth rates of estrogen receptor positive mammary adenocarcinomas are increased in the presence of estrogens. Treatments altering endogenous estrogen synthesis in breast tissues would be highly desirable.
Effects of conjugated linoleic acid (CLA), but not linoleic acid, include inhibition of proliferation and induction of apoptosis in primary rat mammary epithelial cultures (23). In 3T3-L1 cultures of preadipocytes, CLA reportedly inhibits proliferation but stimulates differentiation, i.e., as judged by cellular lipid filling (24,25). Correlations have recently been reported between concentration of fatty acids in adipose tissue in breast cancer patients and adipocyte size in breast tissues (26). Dietary supplementation of lactating Holstein cows with 2.2% safflower oil (containing linoleic and linolenic acid) reportedly increased milk production and quantities of C
18:0
, C
18:1
and C
18:2
fatty acids
Di Nola-Baron Liliana
Page Thurman K.
Sundsmo John S.
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