Title of Invention	A PHARMACEUTICAL PREPARATION FOR PREVENTING ADULT DISEASES
Abstract	A perinatal strategy or method of preventing adult diseases: obesity, hypertension, diabetes mellitus, coronary heart disease, lymphomas and leukemias in later life and improving higher cognitive function and memory and also preventing the development of dementias and Alzheimer"s disease is described which involves supplementation of LCPUFAs: GLA, DGLA, AA, EPA and DHA to the infant from birth till 5 years of age and also to the pregnant women from 2nd trimester of pregnancy onwards. Giving these LCPUFAs from the 2nd trimester of pregnancy to the pregnant mother and to the newborn till 5 years of age post-term, which is considered as the critical period of growth, will ensure the prevention or postponement of the development of the above mentioned adult diseases. It is also suggested that these LCPUFAs need to be given even during the adult age to continue to get the benefit of this perinatal feeding (of these LCPUFAs).

Title of Invention

A PHARMACEUTICAL PREPARATION FOR PREVENTING ADULT DISEASES

Abstract

A perinatal strategy or method of preventing adult diseases: obesity, hypertension, diabetes mellitus, coronary heart disease, lymphomas and leukemias in later life and improving higher cognitive function and memory and also preventing the development of dementias and Alzheimer"s disease is described which involves supplementation of LCPUFAs: GLA, DGLA, AA, EPA and DHA to the infant from birth till 5 years of age and also to the pregnant women from 2nd trimester of pregnancy onwards. Giving these LCPUFAs from the 2nd trimester of pregnancy to the pregnant mother and to the newborn till 5 years of age post-term, which is considered as the critical period of growth, will ensure the prevention or postponement of the development of the above mentioned adult diseases. It is also suggested that these LCPUFAs need to be given even during the adult age to continue to get the benefit of this perinatal feeding (of these LCPUFAs).

Full Text	The invention generally relates to a perinatal strategy or method of preventing or post-pone the development of adult diseases: obesity, insulin resistance, hypertension, diabetes mellitus both type 1 and type 2, coronary heart disease, lymphomas, leukemias, dementia, Alzheimer's disease and to improve cognitive functions. Background of the Invention Stimuli or insults during critical or sensitive periods of early life can have lifetime consequences and has been termed "^programming"(l). Early nutrition can be one important environmental programming factor. Studies showed that nutrition in infancy or fetal life induces lifetime effects on metabolism, growth, and neurodevelopment and on major disease processes such as obesity, hypertension, diabetes, atherosclerosis, and intelligence. It was suggested that fetal and postnatal nutrition is important for nutritional programming (2). Studies showed that infant nutrition in primates programmed later obesity (3), and atherosclerosis (4). Human epidemiological studies indicated that postnatal factors such as breast-feeding are related to later CHD (5). Thus, perinatal nutrition is related to the development of obesity, hypertension, insulin resistance, typel and type 2 diabetes mellitus, lymphomas and leukemias and Alzheimer's disease in later life. Perinatal nutrition can also influence the growth and development of the brain and so the cognitive functions. Hence, if strategies are developed to improve brain growth and the development in general in the perinatal period it is possible to prevent or post-pone the development of the adult diseases: obesity, insulin resistance, hypertension, type 1 and type 2 diabetes mellitus, Alzheimer's disease, dementia, and improve the cognitive functions both in the children and adults. In this context, it is interesting to note that exclusive breast-feeding protects against the development of adult diseases: insulin resistance, obesity, hypertension and type 2 diabetes mellitus, and decreases the risk of CHD in later life (6-8). The exact reason for this beneficial action of breast-feeding is not known. Breast milk is rich in linoleic acid (LA, 18:2 a)-6), gamma-linolenic acid (GLA, 18:3 co-6), arachidonic acid (AA, 20:4 (o-6), a-linolenic acid (ALA, 18:3 co-3), eicosapentaenoic acid (EPA, 20:5 co-3) and docosahexaenoic acid (DHA, 22:6 co-3). Earlier, the inventor suggested that the decreased incidence of adult diseases in breast-fed subjects could be attributed to its high content of both co-6 and co-3 long-chain polyunsaturated fatty acids ((o-6 and co-3 PUFAs) (9). Breast-feeding and adult diseases Obesity Breast-fed infants are protected against the development of obesity in childhood and adults. In a large scale epidemiological study on the impact of breastfeeding on the risk of overweight or obesity, a consistent, protective, and dose dependent effect of breast-feeding was noticed: the longer the duration of breastfeeding the lower the incidence of overweight or obesity (10). Signitlcantly higher plasma concentrations of insulin in infants who had been bottle-fed compared to those who had been breast-fed has been described. Higher insulin concentrations stimulate fat deposition and the early development of adipocytes, which can lead to obesity. Earlier, it was suggested that polyunsaturated fatty acids present in breast milk could be responsible for the decreased incidence of obesity in breast-fed infants. PUFAs are essential for brain growth and development, modulate the actions of various neurotransmitters, and show anti-inflammatory actions (11). Genetically obese (ob/ob) mice showed decreased DGLA, EPA and DHA m their liver phospholipid fraction. These animals when fed EPA and DHA showed reduced weight gain compared to the control suggesting that PUFAs have a role in obesity. In addition, EPA and DHA regulate leptin gene expression (12) and inclusion of AA and DHA in the diet during the first 18 days of life increases several biologically active anandamides in the brain, which in turn can bind to endogenous cannabinoid receptors and regulate food intake. The fact that (a) breast milk is rich in these fatty acids, (b) breast-feeding protects against the development of obesity, and (c) AA, EPA, and DHA supplementation during the neonatal period influences the concentrations of neurotransmitters dopamine, serotonin, and neuropeptide Y (NPY) in various regions of the brain (11, 13) which have an important role in the control of appetite, hunger, satiety, and secretion of insulin from the pancreas events that have profound affect on obesity, suggests that these fatty acids given during infancy prevents obesity. Insulin resistance Insulin resistance and hyperinsulinemia are present in obesity, type 2 diabetes, hypertension, hyperlipidemia, CHD, and in metabolic syndrome X. Insulin resistance is present in formula-fed infants but not in breast-fed (14). Subjects who were bottle-fed had a higher mean 120-minute plasma glucose concentration after a standard oral glucose tolerance test than those who were exclusively breast-fed. Infants who had been bottle-fed showed significantly higher plasma concentrations of insulin compared to those who had been breast-fed (15); higher concentrations of insulin are a sign of insulin resistance. Thus, breast-feeding prevents the development of insulin resistance in adulthood. PUFAs, especially AA, EPA and DHA, augment eNO production both in vitro and in vivo (16). Insulin stimulates eNO production (17). Insulin also suppresses the production of TNF-a production, which has a significant role in insulin resistance. PUFAs attenuate insulin resistance by suppressing TNF-a production and by increasing cell membrane fluidity, which enhances the number of insulin receptors on the membrane and their affinity to insulin (18). Insulin stimulates A^ and A^-desaturases and thus enhances the formation of various PUFAs (19). Thus, there is a close interaction between insulin, PUFAs, TNF-a and the development of insulin resistance. When adequate amounts of PUFAs are not incorporated in the cell membrane, this leads to an increase in the rigidity of cell membrane, resulting in a decrease in the number of insulin receptors and insulin affinity to its receptors, increase in the synthesis and release of TNF-a, and a fall in the ability of endothelial cells to produce NO, events that ultimately lead to insulin resistance. Insulin resistance and hypertension induced in a fructose-fed rat model can be ameliorated by feeding them with EPA and DHA rich oil (20). Highly purified EPA ethyl ester reduced insulin resistance and decreased the incidence of type 2 diabetes in OLETF and WBN/Kob rats, which was associated with changes in the phospholipid fatty acid composition of the skeletal muscle membrane. A significant correlation was noted between insulin secretion and action and AA in healthy humans (21). Fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individual PUFAs in the phospholipid fraction of muscle, particularly AA. In normal men, insulin sensitivity was positively correlated with the percentage of A A in muscle, the total percentage of C20-22 PUFAs, the average degree of fatty acid unsaturation, and the ratio of AA to DGLA, an index of A^ desaturase activity (22). These results suggest that decreased insulin sensitivity is associated with decreased concentrations of both 0-6 and co-3 PUFAs in skeletal muscle phospholipids. Adiponectin, an adipose-specific plasma protein, has anti-atherogenic properties, suppresses adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Its concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. Thiazolidinediones (TZDs), which are synthetic peroxisome proliferator-activated receptor-y (PPAR-y) ligands, significantly increased the plasma adiponectin concentrations in insulin resistant humans (23). PUFAs are natural endogenous ligands for both PPAR-a and PPAR-y (24), suggesting that PUFAs by virtue of their ability to bind to PPAR-a and PPAR-y enhance the concentrations of adiponectin and thus, ameliorate insulin resistance. Blood pressure Breast-fed subjects showed lower blood pressure in later life. In prematurely born children, breast-feeding was associated with lower later blood pressure. These results suggest that high blood pressure in later life has early nutritional origins. Wilson e( al (25) observed that the type of milk feeding influence blood pressure, with breast-feeding being associated with lower systolic pressure. Sprague-Dawley rats made o>3 PUFA deficient (especially DHA) during the perinatal period showed raised blood pressure later in life, even when animals were subsequently repleted with this fatty acid t26). This suggests that perinatal supplementation 0^ PUFAs (AA, EPA, and DHA) prevents hypertension in adult life. Diabetes mellitus Subjects who were exclusively breast-fed for the first 2 months had significantly lower rates of type 2 diabetes compared with those exclusively bottle-fed (27). This decreased incidence of diabetes in breast-fed subjects can be related to the presence of PUFAs in human milk. The inventor reported that when 4-5 week old Wistar rats were pre-treated with AA, EPA, and DHA (24 hours before the intraperitoneal injection of alloxan) prevented damage to pancreatic P cells (28, 29), suggesting that PUFAs prevent the development of typel diabetes. Coronary heart disease (CHD) Obesity, insulin resistance, hypertension, and type 2 diabetes mellitus influence cardiovascular disease. Several studies suggested the adverse effect of formula feed consumption on important risk factors for CHD (10, 30). Breast-fed baboons when given a Western style high saturated fat diet had more early atherosclerotic changes in adulthood than formula-fed animals. This suggests that breast-feeding programmes baboons and humans to be conservative with cholesterol-perhaps appropriately for their normal diet (breast milk)-but it is the high fat Western diet that leads to arterial disease. Based on this, it is suggested that to continue to derive the benefits of breast-feeding it is necessary to consume the same type and amounts of lipids that are present in breast milk, namely the PUFAs. Cognitive development and Alzheimer's disease In humans, the critical spurt in brain growth is between the 3'"'* trimester and 2 years post-term. Pre-term infants are particularly vulnerable to sub-optimal early nutrition in terms of their cognitive performance-notably, language based skills-at 7 '/2-8 years, when cognitive scores are highly predictive of adult ones. PUFAs have important effects on membrane and cellular properties of neural tissue and are preferentially accumulated by the brain during the last trimester of pregnancy and the first months of life (31). The breast-fed babies have a better IQ compared to feed. The concentrations of PUFAs in plasma, red blood cell, and cerebral cortex are lower in formula-fed infants than they are in infants who were breast-fed or formula supplemented with PUFAs. When infant cognitive behavior was assessed at 10 months of age following the supplementation of infant feed formula containing PUFAs containing mainly AA and DHA from birth to age 4 months, they showed significantly more intentional solutions than infants who received formula with no PUFAs. This led to the suggestion that supplementation with PUFAs may be important for the development of childhood intelligence. Thus, improvement in cognitive function observed in breast-fed infants could be due to the high LCPUFA content of breast milk. Low serum levels of DHA could be a risk factor for Alzheimer's disease (32). PUFAs protect neurons directly by preventing neuronal apoptosis and suppressing the production of neurotoxic TNF. Thus, PUFAs are beneficial in Alzheimer's disease and other dementias. It was reported that (0-3 fatty acids produced significant favorable effects in learning (33), suggesting that DHA and EPA are useful in the treatment of memory disorders. Fetal growth retardation, cytokines, PUFAs, and adult diseases AA is important for fetal and postnatal growth. A randomized, masked, controlled trial showed a benefit of supplementing AA + DHA to premature infants on growth, visTial acuity and multiple indices of development (34). Maternal protein restriction decreased A^-desaturase activity, an enzyme necessary for the formation of PUFAs from their precursors, in the low protein offspring (35). Low levels of PUFAs can not only lead to an increase in plasma total and LDL cholesterol levels in the offspring but also to an elevation in the concentrations of TNF-a, due to the absence of the negative feed back control exerted by PUFAs. Prenatal exposure to TNF-a results in obesity (36) and obese children and adults have high plasma TNF-a concentrations (13). Summary of the invention: All the above facts and observations attest to the fact that non-availability or deficiency of various PUFAs in the right combination during the perinatal period could predispose an individual to develop various adult diseases such as obesity, hypertension, diabetes mellitus, CHD, Alzheimer's disease, dementia, certain cancers such as leukemias and lymphomas. This is supported by the observation that adequate breast-feeding protects against the development of obesity in childhood and adults, A consistent, protective, and dose dependent effect of breast-feeding was noticed: the longer the duration of breast-feeding the lower the incidence of overweight or obesity. The reduced risk of overweight and obesity seen in the breast-fed is related to its unique LCPUFA content. •«• Breast-feeding has been associated with lower blood pressure in later life. This is suggests that high blood pressure in later life is due to decreased availability of PUFAs during infancy. As already discussed above, a significantly higher plasma concentrations of insulin in infants who had been bottle-fed than in infants who had been breast-fed was noted; these higher concentrations suggest the development of insulin resistance, suggesting that breast-feeding prevents the development of insulin resistance in adulthood. It is evident from this that breast-feeding prevents the development of insulin resistance, obesity, hypertension, diabetes mellitus, and CHD in adulthood. The inventor proposes that the unique fatty acid profile of human milk can cause structural and/or metabolic changes that prevent the development of obesity, blood pressure, diabetes, and CHD in later life. Elevated plasma TNF-a levels were associated with obesity and insulin resistance, hypertriglyceridemia and glucose intolerance, and hyperleptinemia. Long-chain polyunsaturated fatty acids (PUFAs) such as gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) inhibit the production of TNF-a. It is suggested that supplementation of these PUFAs during the critical periods of growth will prevent insulin resistance, obesity, hypertension, diabetes, CHD in adult life and improve cognitive functions. Hence, perinatal feeding of appropriate amounts of various PUFAs reduce the incidence of insulin resistance, obesity, diabetes mellitus (both type 1 and type 2), hypertension, CHD, lymphomas, leukemias and also improve brain growth and development and improve cognitive functions. Infants have limited capability to synthesize GLA, DGLA, AA, EPA and DHA from LA and ALA in the early stages of life especially, in pre-term infants. Hence, the amounts of PUFAs formed may be inadequate to support the optimal neural development. As a result these infants will have sub-optimal concentrations of PUFAs during this phase of fetal and infant growth that will render them susceptible to develop obesity, hypertension, insulin resistance, diabetes mellitus, lymphomas, leukemias in adult life. They will also have decreased cognitive functions as a result of this sub-optimal concentrations of these PUFAs: GLA, DGLA, AA, EPA and DHA. Perinatal supplementation of PUFAs such as GLA, DGLA, AA, EPA, DHA in combination and in correct proportion and ratio can prevent or post-pone the development of insulin resistance, obesity, diabetes, hypertension, CHD, lymphomas, leukemias, and other proliferative diseases, neurological conditions such as dementias including Alzheimer's disease. Such a supplementation of PUFAs during the perinatal period increases the growth and development of brain and consequently improves the cognitive functions such as intelligence, and memory (since PUFAs are also essential for brain growth and development). These PUFAs can be given during the perinatal period by adding to the infant feed formula, by giving them as supplements to pregnant mother and lactating mothers so that they reach the infant through the breast milk or can be given as oral supplementation in food, mixed with oral drinks, parenteral route, through skin and/or through rectal route. PUFAs supplementation should be given from birth till 5 years post-term and also to the pregnant mothers from the 2"^ trimester onwards (which is considered as the period for the growth of the brain) to prevent or post-pone the development of adult diseases: obesity, insulin resistance, hypertension, diabetes mellitus, lymphomas and leukemias and also improve memory and intelligence and prevent neurological conditions such as dementias and Alzheimer's disease. Since brain keeps producing neurons even in adulthood, these PUFAs have to be given even after the age of 2 to 5 years continuously even to adults to prevent the development of these adult diseases and to prevent Alzheimer's disease. The present invention teaches the use of various PUFAs such as GLA, DGLA, AA, DPA (docosapentaenoic acid), EPA and DHA all together or a combination there of to prevent adult diseases which include: obesity, hypertension, insulin resistance, diabetes mellitus, coronary heart disease, dementias, Alzheimer's disease, and also to improve cognitive functions both in the child and adult. The proportion of various PUFAs can be preferably as under: GLA: DGLA: AA: DPA: EPA: DHA = 0.1-5: 0.05 -10: 0.2-15: O.I -5: 0.2 - 10: 0.2 - 10. To obtain optimum benefit of this combination of various PUFAs in the growth and development of brain and to prevent dementias and Alzheimer's disease it may be necessary to give a minimum combination of GLA, DGLA, AA, EPA and DHA in a proportion of 1: 2: 2.5: L5: 1.5. It is also possible to obtain the benefit of these PUFAs even when only 3 or 4 of these lipid substances are used such as AA, EPA and DHA in a proportion as described above. These PUFAs can be given to the pregnant mothers orally, as an injectable preparation or as rectally or intra-dermally. This preparation of PUFAs can be given to the infants and children as powder, capsule, or mi.xed in water, juices, food either orally or parentarally. For adults this preparation can be given orally or as a parentaral preparation. This can be given once a day, several times a day, weekly or monthly depending on the necessity. This preparation of PUFAs can be given to prevent, post-pone or even after the development of the various diseases as detailed above. BRIEF DESCRIPTION OF THE ILLUSTRATIONS A more detailed understanding of the invention may be had from the following description of preferred embodiments, given by way of example, and to be understood in conjunction with the accompanying illustrations/drawings wherein: FIG. 1 illustrates the structural metabolism of essential fatty acids. DETAILED DESCRIPTION The patent, scientific and medical publications referred to herein establish knowledge that was available to those of ordinary skill in the art at the time the invention was made. The entire disclosures of the issued U.S. patents, published and pending patent applications, and other references cited herein are hereby incorporated by reference. FIG. 1 shows a typical known metabolism pattern of essential fatty acids as known in prior art. Essential fatty acids are precursors of eicosanoids and are important structural components of cell membranes. Definitions In order to more clearly and consistently describe the subject matter which is the invention, the following definitions are provided for certain terms which are useftjl in the specification and appended claims. Metabolism ofessential fatty acids, definition of polyunsaturated fatty acids and long-chain polyunsaturated fattv acids The polyunsaturated fatty acids (PUFAs) are fatty acids having at least two carbon-to-carbon double bonds in a hydrophobic hydrocarbon chain, which typically includes X-Y carbon atoms and terminates in a carboxylic acid group. The PUFAs are classified in accordance with a short hand nomenclature, which designates the number of carbon atoms present (chain length), the number of double bonds in the chain and the position of double bonds nearest to the terminal methyl group. The notation "a: b" is used to denote the chain length and number of double bonds, and the notation "n-x'* is used to describe the position of the double bond nearest to the methyl group. There are 4 independent families of PUFAs, depending on the parent fatty acid from which they are synthesized. They are: (l)The "n-3" series derived from alpha-linolenic acid (ALA, 18:3, n-3). (2) The "n-6" scries derived from linoleic acid (LA, 18:2, n-6). (3) The "n-9" scries derived from oleic acid (OA, 18:1, n-9). (4) The "n-7" series derived from palmitoleic acid (PA, 16:1, n-7). Mammals cannot synthesize the parent fatty acids of the n-3 and n-6 series, and hence they ace often referred to as "essential fatty acids" (EFAs). Because these compounds are necessary for normal health but cannot be synthesized by the human body, they must be obtained through the diet. Both LA and ALA are metabolized by the same set of enzymes. LA is converted to gamma-linolenic acid (GLA, 18:3, n-6) by the action of the enzyme delta-6-desaturase (d-6-d), and GLA is elongated to form di-homo-GLA (DGLA, 20:3, n-6), the precursor of the 1 series of prostaglandins. The reattion catalyzed by d-6-d is the rate-limiting step in the metabolism of EFAs. DGLA can also be converted to arachidonic acid (AA, 20:4, n-6)) by the action of the enzyme delta-5-dcsaturase (d-5-d). AA forms the precursor of 2 series of prostaglandins, thromboxanes and the 4 series leukotrienes. ALA is converted to eicosapentaenoic acid (EPA, 20:5, n-3) by d-6-d and d-5-d. EPA forms the precursor of the 3 series of prostaglandins and the 5 series of leukotrienes. LA, GLA, DGLA, AA, ALA, EPA, docosapcntaenoic acid, and docosahexaenoic acid (DHA, 22:6, n-3) are all PUFAs, but only LA and ALA are EFAs. As used herein, the term "polyunsaturated fatty acid' and the abbreviation "PUFA" mean any acid derived from fats by hydrolysis, or any long-chain (at least 12 carbons) organic acid derived, having at least two carbon-to-carbon double bonds. Examples of PUFAs include but not limited to linoleic acid and arachidonic acid (sec Figure 1 for metabolism of essential fatty acids). The present invention is dependent, in part, upon the discovery of the novel and highly beneficial action of PUFAs to induce selective suppression of free radical generation and TNF-a, IL-1, and lL-6 in the damaged tissues/organs. The invention in one aspect provides methods of inhibiting free radical generation and TNF-a, IL-1, and IL-6 specifically in infiamed tissues such that inflammatory conditions such as rheumatoid arthritis, lupus, progressive systemic sclerosis (PSS), mixed connective tissue disorder (MCTD), and vasculitis can be treated effectively and expeditiously. The invention in another aspect provides methods for preventing and treating various low-grade systemic inflammatory conditions such as insulin resistance syndrome, obesity, type 2 diabetes mellitus, hypertension, hyperlipidemias, coronary heart disease, peripheral vascular disease, and congestive cardiac failure. In all these conditions, the cellular content of PUFAs is low. PUFAs when given in the right combination and proportion are effective in the treatment of these conditions, partly, by enhancing tissue levels of nitric oxide and decreasing lipid peroxide content in these tissues. The invention in another aspect provides methods for preventing and treating cell proliferative disorders including cancer, and other disorders caused by uncontrolled angiogenic activity such as proliferative diabetic retinopathy; and macular degeneration. These conditions are characterized by low-grade inflammation. angiogcnesis, and enhanced lipid peroxidation process. PUFAs kill tumor cells, and also have anti-angiogenic actions and thus inhibit cancer growth. The invention in another aspect provides methods of preventing and treating central nervous system disorders dementia, Alzheimer's disease, schizophrenia, and bipolar disorders. In these diseases also there is low-grade systemic inflammation, enhanced levels of TNF-a, IL-1, IL-6, increased lipid peroxides, and decreased nitric oxide levels. PUFAs when are given during the perinatal period are able to rectify inflammation, angiogcnesis, and enhanced lipid peroxidation process and correct these abnormalities and prevent, arrest or even reverse the course of these diseases. In another aspect, the invention provides methods of preventing the development of psoriasis, and various forms of proliferative glomerulonephritis in which cell proliferation and angiogcnesis plays a dominant role. PUFAs when given during the perinatal period prevent, arrest or even reverse the course of these diseases by inhibiting effectively the expression of abnormal genes, enhancing nitric oxide levels, lowering tissue lipid peroxides and normalizing the PUFA cbntent in the diseased tissues. Although the invention is described primarily as it relates to humans, it is envisaged that the methods of the invention are equally applicable to other mammals, including large domesticated mammals (e.g., race horses, breeding cattle) and smaller domesticated animals (e.g., house pets). Choice of PUFA The present invention employs PUFAs, preferably in the form of salts in various clinical conditions enumerated above. Preferred PUFAs include, but are not limited to, GLA, AA, DHA, EPA, DGLA, ALA, LA, CLA, cis-parinaric acid, and alpha-lipoic acid. Other preferred PUFAs include derivatives of the aforementioned PUFAs, including glycerides, esters, ethers, amides, or phospholipids, or alkylated, alkoxylated, halogcnated, sulfonated, or phosphorylated forms of the fatty acid. In most preferred embodiments, the PUFA is GLA, AA, EPA or DHA. The PUFA is preferably used in the form of a salt solution. Suitable salts include salts of a PUFA with a cation of a small organic group (e.g., ammonium) or a small inorganic group (e.g., an alkali metal or alkali earth metal). Preferred referred salts are those between a PUFA and an alkali metal (e.g., lithium, sodium, potassium), an alkali earth metal (e.g., magnesium, calcium) or a multivalent metal (e.g., manganese, iron, copper, aluminum, zinc, chromium, cobalt, nickel). Most preferred are salts of lithium, sodium, magnesium, manganese, iron, copper, and iodides. Combinations of salts may also be employed. Mechanism of action ot PUFAs The inventor found that polyunsaturated fatty acids such as LA, GLA, AA, ALA, DF'A, EPA, and DHA inhibited leukocyte ACE activity when tested at 10 \|ig/ml concentration (leukocytes used were I x 10^ cells) in vitro (Kumar, K.V. and Das, U.N. (1997), Proc. Soc. Exp. Biol. Med. 214: 374-379). All the PUFAs inhibited the activity of purified ACE enzyme in vitro. This suggests that PUFAs may function as endogenous regulators of ACE activity and thus regulate the formation of Ang-II concentrations in various tissues/organs. PUFAs also enhance nitric oxide generation. Hence, when cell/tissue concentrations of PUFAs are low, the activity of ACE will be high leading to the formation of increased amounts of Ang-ll that in turn leads to increased generation of free radicals that can damage the tissues and program them to develop various adult diseases, especially if this deficiency of PUFAs occurs during the perinatal period, a period that is critical for tissue and organ formation. Invcntor observcd that PUPA levels are low in various clinical conditions such as hypertension, diabetes mellitus, renal diseases, intlammatory conditions like rheumatoid arthritis, lupus; skin disorders such as psoriasis, eczema, atopic and non-atopic dermatitis; atherosclerosis, insulin resistance, obesity; psychiatric conditions such as dementia, schizophrenia, bipolar disorders, memory formation, Alzheimer's disease; and cancer (reviewed and summarized in 9) Thus, in insulin resistance syndrome, obesity, type 2 diabetes mellitus, hypertension, hyperlipidemias, coronary heart disease, peripheral vascular disease, congestive cardiac failure; inflammatory conditions; cancer, disorders caused b> uncontrolled angiogenic activity such as proliferative diabetic retinopathy; macular degeneration, glaucoma, and Alzheimer's disease, schizophrenia, bipolar disorders, psoriasis, various forms of proliferative glomerulonephritis, there occurs low PI FA content in the diseased tissues/organs. Furthermore, high levels of Ang-II and increased ACE enzyme activity also occur. This results in NADPH o.xidase activii\ and enhanced -formation of free radicals and decreased nitric oxide in these cells/tissues. Further, enhanced activity of ACE and Ang-II levels also leads to increased generation ofllMF-a, IL-1, and IL-6, which induce local intlammation aiv; perpetuate tissue damage. Furthermore, when the cell/tissue content of PUFAs is low, cell membrane becomes more rigid and this alters the number of receptors for Ang-ll, insulin, and various neurotransmitters in both peripheral cells and brain cells. In addition. PI FA deficiency leads to decreased formation of the highly beneficial nitric oxide, since PUFAs under normal conditions enhance nitric oxide generation (Das (2001) Nutrition 17: 337-346; Das UN (2000) Prostaglandins Leukot. Essen. Fatty AcuLs 63: 351-362). Based on this, it is suggested that in the presence of adequate amounts of PUFAs, the action of various important molecules such as Ang-Il, nitric oxide, and various neurotransmitters will be optimal so that adult diseases would not occur Furthermore, inventor observed that PUFA deficiency would increase the formation ofTNF-a, lL-1, and IL-6 (called as cytokines) since PUFAs function as negative controllers of cytokine formation. This initiates and perpetuates local inflammation leading to several diseases that have been enumerated above. The present invention provides methods of selectively enhancing intracellular concentrations of PUFAs and simultaneously decreasing ACE activity and Ang-11 levels, optimi^ng the actions of insulin, and various neurotransmitters in the diseased cclls/tissues/organs such that various adult diseases would not occur and/or pre\ented from developing. PUFAs given during the perinatal period are easily internali/ed into cells, and this results in increase in the cellular levels of PUFAs, increase in nitne oxide generation, and pro-inflammatory cytokines, and significant decrease in local inflammation and thus, prevention of adult diseases. Methods of Administration Examples Hard gelatin capsules or soft gelatin capsules made by accepted normal or forms or methods containing various PUFA in the desired combination and proportuMi and arc administered orally to pregnant women, lactating women, and young uomcn in their active reproductive period and are administered orally to children from the age of 1 year to 12 years. A solution containing various PUFAs in the desired combination and proportion and are administered orally to infants from the age of 3 months till 2 vears of age. A free flowing powder containing various PUFAs in the desired combination and proportion and in microencapsulated form is administered orally to newborn from the age of few days till the age of 2 years by mixing it with milk, water, food, and other eatables CTr with fruit juices, and in any other suitable means to enhance their t growth and development. References: 1. Lucas A. Programming by early nutrition in man. In: Block GR, Whelan J. Eds. The childhood environment and adult disease. Chichester: Wiley, 1091: 38-55 (CIBA Foundation Symposium 156). 2. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease-the h>pothesis rcvisitc?d. BMJ 319: 245-249, 1999. , 3. Lewis DS, Bertrand HA, McMahan CA, et al. Prevveaning food intake influences the adiposity of young adult baboons. J Clin Invest 78: 899-'-)()5, 1986. 4. Lewis DS, Mott GE, McMahan CA, et al. Deferred effects of prewcaning diet on atherosclerosis in adolescent baboons. Arteriosclerosis 8: 274-180, 1^88. 5. Fall CHD, Barker DJP, Osmond C, etal. Relation of infant feeding to adult serum cholesterol concentration and death from ischemic heart disease. BMJ 304: 801-805, 1992. 6. Ravelli AC, van der Meulen JH, Osmond C, et al. Infant feeding and adult glucose tolerance, lipid profile, blood pressure, and obesity. Arch Dis Child 82: 248-252, 2000. 7. Singhal A., Cole T J, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomized trials. Lancet 357: 413-419, 2001. 8. von Kries R, Koletzko B, Sauerwald T, et al. Breast feeding and obesit\: eros^ sectional study. BMJ 319: 147-150, 1999. 9. Das UN. A Perinatal Strategy to Prevent Adult Disease: The role of IJ)N 10. Das UN. Pathophysiology of metabolic syndrome X and its links to the perinatal period. Nutrition 21: 762-773, 2005 11. Lucas A, Sarson DL, Blackburn AM, et al. Breast vs bottle: endocrine responses are different with formula feeding. Lancet i: 1267-1269, 1980. 12. Das UN. Is obesity an inflammatory condition? Nutrition 17: 953-966, 2001 - 13. Reseland JB, Maugen F, HoUung K, et al. Reduction of leptin gene expression by dietary polyunsaturated fatty acids. J Lipid Res 42: 743-750, 2001. 14. de la Prcsa Owens S, Innis SM. Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and a-linolenic acid deficient diet in formula-fed piglets. J Nutr 129: 2088-2093, 1999. 15. Wallenseen M, Lindblad BS, Zetterstrom R, Persson B. Acute C-peptidc. insulin and branched chain amino acid response to feeding in formula and breast-fed infants. Acta PaediatrScand 80: 143-148, 1991. 16. Das UN. Is insulin an anti-intlammatory molecule? Nutrition 17: 40-)-4r>. 2001. 17. Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vi\o: a specific vascular action of insulin. Circulation 101: 676-681, 2000. 18. Das UN. Insulin resistance and hyperinsulinemia: Are they secondar\ to an alteration in the metabolism of essential fatty acids? Med Sci Res 22: 243-24\ 1994. 19. Das UN. essential fatty acids: biology and their clinical implications. Asian F^acific J Pharmacol 6: 317-330, 1991. 20. 1 luang Y-J, Fang VS, Chou Y-C, et al. Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation. Metabolism 46: 1252-1258, 1997. 21. Pelikanova T, Kohout M, Valek J, et al. Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men. Metabolism 38: 188-192, 1989. 22. Borkman M, Storlien LH, Pan DA, et al. The relation between insulin sensitivity and the fatty acid composition of skeletal muscle phospholipids. \ Engl J Med 328: 238-244, 1993. 23. Maeda N, Takahashi M, Funahashi T, et al. PPARy ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50: 2094-2099, 2001. 24. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome prolifcrator-activated receptors a and y. Proc Natl Acad Sci USA 94: 43 1 S-4323, 1997. 25. Wilson AC, Forsyth JS, Greene SA, et al. Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. BMJ 316:21-25, 1998. 26. Weisinger US, Armitage JA, Sinclair AJ, et al. Perinatal omega-3 detkicnc\ affects blood pressure in later in life. Nature Med 7: 258-259, 2001. 27. Pcttitt DJ, Forman MR, Hanson RL, et al. Breastfeeding and incidence o\ non-insulin-depcndent diabetes mellitus in Pima Indians. Lancet 350: 166-H)8, 1997. 28. Suresh Y, Das UN. Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot Essen Fatt\ Acids 64: 37-52,2001. 29. Mohan IK, Das UN. Prevention of chemically induced diabetes mellitus in experiiflental animals by polyunsaturated fatty acids. Nu,trition 17: 126-1^1, 2001. 30. I-all CUD, Barker DJP, Osmond C, etal. Relation of infant feeding to adult serum cholesterol concentration and death from ischemic heart disease BMJ 304:801-805, 1992. 31. Martinez M. Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr 120: S129-S138, 1992. 32. Kyle DJ, Schaefer E, Patton G, Beiser A. Low serum docosahexaenoic acid is significant risk factor for Alzheimer's disease. Lipids 34: S245, 1999. 33. Yehuda S, Carasso RL. Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified a-linolenic and linoleic acids: determination of the optimal \v3-to-vv6 ratio. Proc Natl Acad sc USA 90: 10345-10349, 1993. 34. O'Connor DL, et al. and on behalf of the Preterm Lipid Study. Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: A prospective, randomized controlled trial. Pediatrics 108: 359-371, 2001. 35. Mercuri O, et al. Prenatal protein depletion and delta 9, delta 6, and delta :^ desaturases in the rats. Lipids 14: 822-825, 1979. 36. Dahlgren J, et al. Prenatal cytokine exposure results in obesity and gcndcr-specific programming. Am J Physiol 281: E326-E334, 2001. 1 claim: 1. A pharmaceutical preparation suitable for the prevention of adult diseases using various n-3 and n-6 polyunsaturated fatty acids comprising; cis-linolcic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid. 2. A pharmaceutical preparation according to claim 1, wherein the content of n-() fatty acids cis-linolcic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachidonic acid varies from 0.5 mg to 500 gm. 3. A pharmaceutical preparation according to claim I, wherein the content of n-.'^ alpha-linolenic acid, eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid varies from 0.5 mg to 500 gm. 4. A pharjpaceutical preparation according to claim 1, wherein the ratio bciuecii n-6 cis-linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid and n-3 eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid varies from 0.01: 500 to 500: 0.01. 5. A pharmaceutical preparation according to claim 1, wherein in the form of a fatty acid selected from the group consisting of a free acid, a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a manganese salt, an iron salt, a copper salt, an aluminum salt, a zinc salt, a chromium salt, a cohalt salt, a nickel salt and an iodide and/or in the form of a fatty acid derivative selected from the group consisting of glycerides, esters, free acids, amides, phospholipids and salts. 6. A pharmaceutical preparation according to claim 1, wherein all orsomcofn-n and n-3 fatty acids are derived from oils: evening primrose oil, black current seed oil, cod liver oil, marine fish oil, shark liver oil, and other plants, marine organisms, fungus or bacteria. 7. A pharmaceutical preparation according to claim 6, wherein all or some ot'the n-6 and n-3 fatty acids is dispensed as a oral soft gelatin capsule containing a mixture of oils of plant, animal, fungal, and/or bacterial origin in the desired proportion and quantity. 8. A pharmaceutical preparation according to claim 7, wherein all or some of the n-3 and n-6 fatty acids containing oils are microencapsulated and delivered in a hard gelatin capsule or tablet. 9. A pharmaceutical preparation according to claim 8, wherein all or some of the n-3 and n-6 fatty acids is in the form of a oral liquid containing a pharmaceutically acceptable carrier suitable for addition to food and infant feeds. 10. A pharmaceutical preparation according to claims 6-8 that is administered to men and women, pregnant women and lactating mothers. 11. A pharmaceutical preparation according to claims 6-9 wherein it is administered once a day, twice a day, thrice a day or as frequently as needed.

Full Text

The invention generally relates to a perinatal strategy or method of preventing or post-pone the development of adult diseases: obesity, insulin resistance, hypertension, diabetes mellitus both type 1 and type 2, coronary heart disease, lymphomas, leukemias, dementia, Alzheimer's disease and to improve cognitive functions.
Background of the Invention
Stimuli or insults during critical or sensitive periods of early life can have lifetime consequences and has been termed "^programming"(l). Early nutrition can be one important environmental programming factor. Studies showed that nutrition in infancy or fetal life induces lifetime effects on metabolism, growth, and neurodevelopment and on major disease processes such as obesity, hypertension, diabetes, atherosclerosis, and intelligence. It was suggested that fetal and postnatal nutrition is important for nutritional programming (2). Studies showed that infant nutrition in primates programmed later obesity (3), and atherosclerosis (4). Human epidemiological studies indicated that postnatal factors such as breast-feeding are related to later CHD (5). Thus, perinatal nutrition is related to the development of obesity, hypertension, insulin resistance, typel and type 2 diabetes mellitus, lymphomas and leukemias and Alzheimer's disease in later life. Perinatal nutrition can also influence the growth and development of the brain and so the cognitive functions. Hence, if strategies are developed to improve brain growth and the development in general in the perinatal period it is possible to prevent or post-pone the development of the adult diseases: obesity, insulin resistance, hypertension, type 1 and type 2 diabetes mellitus, Alzheimer's disease, dementia, and improve the cognitive functions both in the children and adults.

In this context, it is interesting to note that exclusive breast-feeding protects against the development of adult diseases: insulin resistance, obesity, hypertension and type 2 diabetes mellitus, and decreases the risk of CHD in later life (6-8). The exact reason for this beneficial action of breast-feeding is not known. Breast milk is rich in linoleic acid (LA, 18:2 a)-6), gamma-linolenic acid (GLA, 18:3 co-6), arachidonic acid (AA, 20:4 (o-6), a-linolenic acid (ALA, 18:3 co-3), eicosapentaenoic acid (EPA, 20:5 co-3) and docosahexaenoic acid (DHA, 22:6 co-3). Earlier, the inventor suggested that the decreased incidence of adult diseases in breast-fed subjects could be attributed to its high content of both co-6 and co-3 long-chain polyunsaturated fatty acids ((o-6 and co-3 PUFAs) (9).
Breast-feeding and adult diseases Obesity
Breast-fed infants are protected against the development of obesity in childhood and adults. In a large scale epidemiological study on the impact of breastfeeding on the risk of overweight or obesity, a consistent, protective, and dose dependent effect of breast-feeding was noticed: the longer the duration of breastfeeding the lower the incidence of overweight or obesity (10). Signitlcantly higher plasma concentrations of insulin in infants who had been bottle-fed compared to those who had been breast-fed has been described. Higher insulin concentrations stimulate fat deposition and the early development of adipocytes, which can lead to obesity. Earlier, it was suggested that polyunsaturated fatty acids present in breast milk could be responsible for the decreased incidence of obesity in breast-fed infants. PUFAs are essential for brain growth and development, modulate the actions of various neurotransmitters, and show anti-inflammatory actions (11). Genetically obese

(ob/ob) mice showed decreased DGLA, EPA and DHA m their liver phospholipid fraction. These animals when fed EPA and DHA showed reduced weight gain compared to the control suggesting that PUFAs have a role in obesity. In addition, EPA and DHA regulate leptin gene expression (12) and inclusion of AA and DHA in the diet during the first 18 days of life increases several biologically active anandamides in the brain, which in turn can bind to endogenous cannabinoid receptors and regulate food intake. The fact that (a) breast milk is rich in these fatty acids, (b) breast-feeding protects against the development of obesity, and (c) AA, EPA, and DHA supplementation during the neonatal period influences the concentrations of neurotransmitters dopamine, serotonin, and neuropeptide Y (NPY) in various regions of the brain (11, 13) which have an important role in the control of appetite, hunger, satiety, and secretion of insulin from the pancreas events that have profound affect on obesity, suggests that these fatty acids given during infancy prevents obesity.
Insulin resistance
Insulin resistance and hyperinsulinemia are present in obesity, type 2 diabetes, hypertension, hyperlipidemia, CHD, and in metabolic syndrome X. Insulin resistance is present in formula-fed infants but not in breast-fed (14). Subjects who were bottle-fed had a higher mean 120-minute plasma glucose concentration after a standard oral glucose tolerance test than those who were exclusively breast-fed. Infants who had been bottle-fed showed significantly higher plasma concentrations of insulin compared to those who had been breast-fed (15); higher concentrations of insulin are a sign of insulin resistance. Thus, breast-feeding prevents the development of insulin resistance in adulthood.

PUFAs, especially AA, EPA and DHA, augment eNO production both in vitro and in vivo (16). Insulin stimulates eNO production (17). Insulin also suppresses the production of TNF-a production, which has a significant role in insulin resistance. PUFAs attenuate insulin resistance by suppressing TNF-a production and by increasing cell membrane fluidity, which enhances the number of insulin receptors on the membrane and their affinity to insulin (18). Insulin stimulates A^ and A^-desaturases and thus enhances the formation of various PUFAs (19). Thus, there is a close interaction between insulin, PUFAs, TNF-a and the development of insulin resistance. When adequate amounts of PUFAs are not incorporated in the cell membrane, this leads to an increase in the rigidity of cell membrane, resulting in a decrease in the number of insulin receptors and insulin affinity to its receptors, increase in the synthesis and release of TNF-a, and a fall in the ability of endothelial cells to produce NO, events that ultimately lead to insulin resistance.
Insulin resistance and hypertension induced in a fructose-fed rat model can be ameliorated by feeding them with EPA and DHA rich oil (20). Highly purified EPA ethyl ester reduced insulin resistance and decreased the incidence of type 2 diabetes in OLETF and WBN/Kob rats, which was associated with changes in the phospholipid fatty acid composition of the skeletal muscle membrane. A significant correlation was noted between insulin secretion and action and AA in healthy humans (21). Fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individual PUFAs in the phospholipid fraction of muscle, particularly AA. In normal men, insulin sensitivity was positively correlated with the percentage of A A in muscle, the total percentage of C20-22 PUFAs, the average degree of fatty acid unsaturation, and the ratio of AA to DGLA, an index of

A^ desaturase activity (22). These results suggest that decreased insulin sensitivity is associated with decreased concentrations of both 0-6 and co-3 PUFAs in skeletal muscle phospholipids.
Adiponectin, an adipose-specific plasma protein, has anti-atherogenic properties, suppresses adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Its concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. Thiazolidinediones (TZDs), which are synthetic peroxisome proliferator-activated receptor-y (PPAR-y) ligands, significantly increased the plasma adiponectin concentrations in insulin resistant humans (23). PUFAs are natural endogenous ligands for both PPAR-a and PPAR-y (24), suggesting that PUFAs by virtue of their ability to bind to PPAR-a and PPAR-y enhance the concentrations of adiponectin and thus, ameliorate insulin resistance.
Blood pressure
Breast-fed subjects showed lower blood pressure in later life. In prematurely born children, breast-feeding was associated with lower later blood pressure. These results suggest that high blood pressure in later life has early nutritional origins. Wilson e( al (25) observed that the type of milk feeding influence blood pressure, with breast-feeding being associated with lower systolic pressure. Sprague-Dawley rats made o>3 PUFA deficient (especially DHA) during the perinatal period showed raised blood pressure later in life, even when animals were subsequently repleted with this fatty acid t26). This suggests that perinatal supplementation 0^ PUFAs (AA, EPA, and DHA) prevents hypertension in adult life.
Diabetes mellitus

Subjects who were exclusively breast-fed for the first 2 months had significantly lower rates of type 2 diabetes compared with those exclusively bottle-fed (27). This decreased incidence of diabetes in breast-fed subjects can be related to the presence of PUFAs in human milk. The inventor reported that when 4-5 week old Wistar rats were pre-treated with AA, EPA, and DHA (24 hours before the intraperitoneal injection of alloxan) prevented damage to pancreatic P cells (28, 29), suggesting that PUFAs prevent the development of typel diabetes.
Coronary heart disease (CHD)
Obesity, insulin resistance, hypertension, and type 2 diabetes mellitus influence cardiovascular disease. Several studies suggested the adverse effect of formula feed consumption on important risk factors for CHD (10, 30). Breast-fed baboons when given a Western style high saturated fat diet had more early atherosclerotic changes in adulthood than formula-fed animals. This suggests that breast-feeding programmes baboons and humans to be conservative with cholesterol-perhaps appropriately for their normal diet (breast milk)-but it is the high fat Western diet that leads to arterial disease. Based on this, it is suggested that to continue to derive the benefits of breast-feeding it is necessary to consume the same type and amounts of lipids that are present in breast milk, namely the PUFAs.
Cognitive development and Alzheimer's disease
In humans, the critical spurt in brain growth is between the 3'"'* trimester and 2 years post-term. Pre-term infants are particularly vulnerable to sub-optimal early nutrition in terms of their cognitive performance-notably, language based skills-at 7 '/2-8 years, when cognitive scores are highly predictive of adult ones.

PUFAs have important effects on membrane and cellular properties of neural tissue and are preferentially accumulated by the brain during the last trimester of pregnancy and the first months of life (31). The breast-fed babies have a better IQ compared to feed. The concentrations of PUFAs in plasma, red blood cell, and cerebral cortex are lower in formula-fed infants than they are in infants who were breast-fed or formula supplemented with PUFAs. When infant cognitive behavior was assessed at 10 months of age following the supplementation of infant feed formula containing PUFAs containing mainly AA and DHA from birth to age 4 months, they showed significantly more intentional solutions than infants who received formula with no PUFAs. This led to the suggestion that supplementation with PUFAs may be important for the development of childhood intelligence. Thus, improvement in cognitive function observed in breast-fed infants could be due to the high LCPUFA content of breast milk.
Low serum levels of DHA could be a risk factor for Alzheimer's disease (32). PUFAs protect neurons directly by preventing neuronal apoptosis and suppressing the production of neurotoxic TNF. Thus, PUFAs are beneficial in Alzheimer's disease and other dementias. It was reported that (0-3 fatty acids produced significant favorable effects in learning (33), suggesting that DHA and EPA are useful in the treatment of memory disorders.
Fetal growth retardation, cytokines, PUFAs, and adult diseases
AA is important for fetal and postnatal growth. A randomized, masked, controlled trial showed a benefit of supplementing AA + DHA to premature infants on growth, visTial acuity and multiple indices of development (34). Maternal protein

restriction decreased A^-desaturase activity, an enzyme necessary for the formation of PUFAs from their precursors, in the low protein offspring (35). Low levels of PUFAs can not only lead to an increase in plasma total and LDL cholesterol levels in the offspring but also to an elevation in the concentrations of TNF-a, due to the absence of the negative feed back control exerted by PUFAs. Prenatal exposure to TNF-a results in obesity (36) and obese children and adults have high plasma TNF-a concentrations (13).
Summary of the invention:
All the above facts and observations attest to the fact that non-availability or deficiency of various PUFAs in the right combination during the perinatal period could predispose an individual to develop various adult diseases such as obesity, hypertension, diabetes mellitus, CHD, Alzheimer's disease, dementia, certain cancers such as leukemias and lymphomas. This is supported by the observation that adequate breast-feeding protects against the development of obesity in childhood and adults, A consistent, protective, and dose dependent effect of breast-feeding was noticed: the longer the duration of breast-feeding the lower the incidence of overweight or obesity. The reduced risk of overweight and obesity seen in the breast-fed is related to its
unique LCPUFA content.
•«• Breast-feeding has been associated with lower blood pressure in later life. This
is suggests that high blood pressure in later life is due to decreased availability of
PUFAs during infancy.
As already discussed above, a significantly higher plasma concentrations of insulin in infants who had been bottle-fed than in infants who had been breast-fed was

noted; these higher concentrations suggest the development of insulin resistance, suggesting that breast-feeding prevents the development of insulin resistance in adulthood. It is evident from this that breast-feeding prevents the development of insulin resistance, obesity, hypertension, diabetes mellitus, and CHD in adulthood. The inventor proposes that the unique fatty acid profile of human milk can cause structural and/or metabolic changes that prevent the development of obesity, blood pressure, diabetes, and CHD in later life.
Elevated plasma TNF-a levels were associated with obesity and insulin resistance, hypertriglyceridemia and glucose intolerance, and hyperleptinemia. Long-chain polyunsaturated fatty acids (PUFAs) such as gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) inhibit the production of TNF-a. It is suggested that supplementation of these PUFAs during the critical periods of growth will prevent insulin resistance, obesity, hypertension, diabetes, CHD in adult life and improve cognitive functions.
Hence, perinatal feeding of appropriate amounts of various PUFAs reduce the incidence of insulin resistance, obesity, diabetes mellitus (both type 1 and type 2), hypertension, CHD, lymphomas, leukemias and also improve brain growth and development and improve cognitive functions. Infants have limited capability to synthesize GLA, DGLA, AA, EPA and DHA from LA and ALA in the early stages of life especially, in pre-term infants. Hence, the amounts of PUFAs formed may be inadequate to support the optimal neural development. As a result these infants will have sub-optimal concentrations of PUFAs during this phase of fetal and infant growth that will render them susceptible to develop obesity, hypertension, insulin

resistance, diabetes mellitus, lymphomas, leukemias in adult life. They will also have decreased cognitive functions as a result of this sub-optimal concentrations of these PUFAs: GLA, DGLA, AA, EPA and DHA.
Perinatal supplementation of PUFAs such as GLA, DGLA, AA, EPA, DHA in combination and in correct proportion and ratio can prevent or post-pone the development of insulin resistance, obesity, diabetes, hypertension, CHD, lymphomas, leukemias, and other proliferative diseases, neurological conditions such as dementias including Alzheimer's disease. Such a supplementation of PUFAs during the perinatal period increases the growth and development of brain and consequently improves the cognitive functions such as intelligence, and memory (since PUFAs are also essential for brain growth and development). These PUFAs can be given during the perinatal period by adding to the infant feed formula, by giving them as supplements to pregnant mother and lactating mothers so that they reach the infant through the breast milk or can be given as oral supplementation in food, mixed with oral drinks, parenteral route, through skin and/or through rectal route. PUFAs supplementation should be given from birth till 5 years post-term and also to the pregnant mothers from the 2"^ trimester onwards (which is considered as the period for the growth of the brain) to prevent or post-pone the development of adult diseases: obesity, insulin resistance, hypertension, diabetes mellitus, lymphomas and leukemias and also improve memory and intelligence and prevent neurological conditions such as dementias and Alzheimer's disease. Since brain keeps producing neurons even in adulthood, these PUFAs have to be given even after the age of 2 to 5 years continuously even to adults to prevent the development of these adult diseases and to prevent Alzheimer's disease.

The present invention teaches the use of various PUFAs such as GLA, DGLA, AA, DPA (docosapentaenoic acid), EPA and DHA all together or a combination there of to prevent adult diseases which include: obesity, hypertension, insulin resistance, diabetes mellitus, coronary heart disease, dementias, Alzheimer's disease, and also to improve cognitive functions both in the child and adult. The proportion of various PUFAs can be preferably as under: GLA: DGLA: AA: DPA: EPA: DHA = 0.1-5: 0.05 -10: 0.2-15: O.I -5: 0.2 - 10: 0.2 - 10. To obtain optimum benefit of this combination of various PUFAs in the growth and development of brain and to prevent dementias and Alzheimer's disease it may be necessary to give a minimum combination of GLA, DGLA, AA, EPA and DHA in a proportion of 1: 2: 2.5: L5: 1.5. It is also possible to obtain the benefit of these PUFAs even when only 3 or 4 of these lipid substances are used such as AA, EPA and DHA in a proportion as described above. These PUFAs can be given to the pregnant mothers orally, as an injectable preparation or as rectally or intra-dermally. This preparation of PUFAs can be given to the infants and children as powder, capsule, or mi.xed in water, juices, food either orally or parentarally. For adults this preparation can be given orally or as a parentaral preparation. This can be given once a day, several times a day, weekly or monthly depending on the necessity. This preparation of PUFAs can be given to prevent, post-pone or even after the development of the various diseases as detailed above.
BRIEF DESCRIPTION OF THE ILLUSTRATIONS
A more detailed understanding of the invention may be had from the following description of preferred embodiments, given by way of example, and to be understood

in conjunction with the accompanying illustrations/drawings wherein: FIG. 1 illustrates the structural metabolism of essential fatty acids.
DETAILED DESCRIPTION
The patent, scientific and medical publications referred to herein establish knowledge that was available to those of ordinary skill in the art at the time the invention was made. The entire disclosures of the issued U.S. patents, published and pending patent applications, and other references cited herein are hereby incorporated by reference.
FIG. 1 shows a typical known metabolism pattern of essential fatty acids as known in prior art. Essential fatty acids are precursors of eicosanoids and are important structural components of cell membranes.
Definitions
In order to more clearly and consistently describe the subject matter which is the invention, the following definitions are provided for certain terms which are useftjl in the specification and appended claims.
Metabolism ofessential fatty acids, definition of polyunsaturated fatty acids and long-chain polyunsaturated fattv acids
The polyunsaturated fatty acids (PUFAs) are fatty acids having at least two carbon-to-carbon double bonds in a hydrophobic hydrocarbon chain, which typically includes X-Y carbon atoms and terminates in a carboxylic acid group. The PUFAs are classified in accordance with a short hand nomenclature, which designates the number of carbon atoms present (chain length), the number of double bonds in the chain and the position of double bonds nearest to the terminal methyl group. The

notation "a: b" is used to denote the chain length and number of double bonds, and the notation "n-x'* is used to describe the position of the double bond nearest to the methyl group. There are 4 independent families of PUFAs, depending on the parent fatty acid from which they are synthesized. They are:
(l)The "n-3" series derived from alpha-linolenic acid (ALA, 18:3, n-3).
(2) The "n-6" scries derived from linoleic acid (LA, 18:2, n-6).
(3) The "n-9" scries derived from oleic acid (OA, 18:1, n-9).
(4) The "n-7" series derived from palmitoleic acid (PA, 16:1, n-7).
Mammals cannot synthesize the parent fatty acids of the n-3 and n-6 series, and hence they ace often referred to as "essential fatty acids" (EFAs). Because these compounds are necessary for normal health but cannot be synthesized by the human body, they must be obtained through the diet.
Both LA and ALA are metabolized by the same set of enzymes. LA is converted to gamma-linolenic acid (GLA, 18:3, n-6) by the action of the enzyme delta-6-desaturase (d-6-d), and GLA is elongated to form di-homo-GLA (DGLA, 20:3, n-6), the precursor of the 1 series of prostaglandins. The reattion catalyzed by d-6-d is the rate-limiting step in the metabolism of EFAs. DGLA can also be converted to arachidonic acid (AA, 20:4, n-6)) by the action of the enzyme delta-5-dcsaturase (d-5-d). AA forms the precursor of 2 series of prostaglandins, thromboxanes and the 4 series leukotrienes. ALA is converted to eicosapentaenoic acid (EPA, 20:5, n-3) by d-6-d and d-5-d. EPA forms the precursor of the 3 series of prostaglandins and the 5 series of leukotrienes. LA, GLA, DGLA, AA, ALA, EPA, docosapcntaenoic acid, and docosahexaenoic acid (DHA, 22:6, n-3) are all PUFAs, but only LA and ALA are EFAs. As used herein, the term "polyunsaturated fatty

acid*' and the abbreviation "PUFA" mean any acid derived from fats by hydrolysis, or any long-chain (at least 12 carbons) organic acid derived, having at least two carbon-to-carbon double bonds. Examples of PUFAs include but not limited to linoleic acid and arachidonic acid (sec Figure 1 for metabolism of essential fatty acids).
The present invention is dependent, in part, upon the discovery of the novel and highly beneficial action of PUFAs to induce selective suppression of free radical generation and TNF-a, IL-1, and lL-6 in the damaged tissues/organs. The invention in one aspect provides methods of inhibiting free radical generation and TNF-a, IL-1, and IL-6 specifically in infiamed tissues such that inflammatory conditions such as rheumatoid arthritis, lupus, progressive systemic sclerosis (PSS), mixed connective tissue disorder (MCTD), and vasculitis can be treated effectively and expeditiously.
The invention in another aspect provides methods for preventing and treating various low-grade systemic inflammatory conditions such as insulin resistance syndrome, obesity, type 2 diabetes mellitus, hypertension, hyperlipidemias, coronary heart disease, peripheral vascular disease, and congestive cardiac failure. In all these conditions, the cellular content of PUFAs is low. PUFAs when given in the right combination and proportion are effective in the treatment of these conditions, partly, by enhancing tissue levels of nitric oxide and decreasing lipid peroxide content in these tissues.
The invention in another aspect provides methods for preventing and treating cell proliferative disorders including cancer, and other disorders caused by uncontrolled angiogenic activity such as proliferative diabetic retinopathy; and macular degeneration. These conditions are characterized by low-grade inflammation.

angiogcnesis, and enhanced lipid peroxidation process. PUFAs kill tumor cells, and also have anti-angiogenic actions and thus inhibit cancer growth.
The invention in another aspect provides methods of preventing and treating central nervous system disorders dementia, Alzheimer's disease, schizophrenia, and bipolar disorders. In these diseases also there is low-grade systemic inflammation, enhanced levels of TNF-a, IL-1, IL-6, increased lipid peroxides, and decreased nitric oxide levels. PUFAs when are given during the perinatal period are able to rectify inflammation, angiogcnesis, and enhanced lipid peroxidation process and correct these abnormalities and prevent, arrest or even reverse the course of these diseases.
In another aspect, the invention provides methods of preventing the development of psoriasis, and various forms of proliferative glomerulonephritis in which cell proliferation and angiogcnesis plays a dominant role. PUFAs when given during the perinatal period prevent, arrest or even reverse the course of these diseases by inhibiting effectively the expression of abnormal genes, enhancing nitric oxide levels, lowering tissue lipid peroxides and normalizing the PUFA cbntent in the diseased tissues.
Although the invention is described primarily as it relates to humans, it is envisaged that the methods of the invention are equally applicable to other mammals, including large domesticated mammals (e.g., race horses, breeding cattle) and smaller domesticated animals (e.g., house pets).
Choice of PUFA
The present invention employs PUFAs, preferably in the form of salts in various clinical conditions enumerated above. Preferred PUFAs include, but are not

limited to, GLA, AA, DHA, EPA, DGLA, ALA, LA, CLA, cis-parinaric acid, and alpha-lipoic acid. Other preferred PUFAs include derivatives of the aforementioned PUFAs, including glycerides, esters, ethers, amides, or phospholipids, or alkylated, alkoxylated, halogcnated, sulfonated, or phosphorylated forms of the fatty acid. In most preferred embodiments, the PUFA is GLA, AA, EPA or DHA.
The PUFA is preferably used in the form of a salt solution. Suitable salts include salts of a PUFA with a cation of a small organic group (e.g., ammonium) or a small inorganic group (e.g., an alkali metal or alkali earth metal). Preferred referred salts are those between a PUFA and an alkali metal (e.g., lithium, sodium, potassium), an alkali earth metal (e.g., magnesium, calcium) or a multivalent metal (e.g., manganese, iron, copper, aluminum, zinc, chromium, cobalt, nickel). Most preferred are salts of lithium, sodium, magnesium, manganese, iron, copper, and iodides. Combinations of salts may also be employed.
Mechanism of action ot PUFAs
The inventor found that polyunsaturated fatty acids such as LA, GLA, AA, ALA, DF'A, EPA, and DHA inhibited leukocyte ACE activity when tested at 10 |ig/ml concentration (leukocytes used were I x 10^ cells) in vitro (Kumar, K.V. and Das, U.N. (1997), Proc. Soc. Exp. Biol. Med. 214: 374-379). All the PUFAs inhibited the activity of purified ACE enzyme in vitro. This suggests that PUFAs may function as endogenous regulators of ACE activity and thus regulate the formation of Ang-II concentrations in various tissues/organs. PUFAs also enhance nitric oxide generation. Hence, when cell/tissue concentrations of PUFAs are low, the activity of ACE will be high leading to the formation of increased amounts of Ang-ll that in turn leads to increased generation of free radicals that can damage the tissues and program them to

develop various adult diseases, especially if this deficiency of PUFAs occurs during the perinatal period, a period that is critical for tissue and organ formation. Invcntor observcd that PUPA levels are low in various clinical conditions such as hypertension, diabetes mellitus, renal diseases, intlammatory conditions like rheumatoid arthritis, lupus; skin disorders such as psoriasis, eczema, atopic and non-atopic dermatitis; atherosclerosis, insulin resistance, obesity; psychiatric conditions such as dementia, schizophrenia, bipolar disorders, memory formation, Alzheimer's disease; and cancer (reviewed and summarized in 9)
Thus, in insulin resistance syndrome, obesity, type 2 diabetes mellitus, hypertension, hyperlipidemias, coronary heart disease, peripheral vascular disease, congestive cardiac failure; inflammatory conditions; cancer, disorders caused b> uncontrolled angiogenic activity such as proliferative diabetic retinopathy; macular degeneration, glaucoma, and Alzheimer's disease, schizophrenia, bipolar disorders, psoriasis, various forms of proliferative glomerulonephritis, there occurs low PI FA content in the diseased tissues/organs. Furthermore, high levels of Ang-II and increased ACE enzyme activity also occur. This results in NADPH o.xidase activii\ and enhanced -formation of free radicals and decreased nitric oxide in these cells/tissues. Further, enhanced activity of ACE and Ang-II levels also leads to increased generation ofllMF-a, IL-1, and IL-6, which induce local intlammation aiv; perpetuate tissue damage.
Furthermore, when the cell/tissue content of PUFAs is low, cell membrane becomes more rigid and this alters the number of receptors for Ang-ll, insulin, and various neurotransmitters in both peripheral cells and brain cells. In addition. PI FA deficiency leads to decreased formation of the highly beneficial nitric oxide, since

PUFAs under normal conditions enhance nitric oxide generation (Das (2001) Nutrition 17: 337-346; Das UN (2000) Prostaglandins Leukot. Essen. Fatty AcuLs 63: 351-362). Based on this, it is suggested that in the presence of adequate amounts of PUFAs, the action of various important molecules such as Ang-Il, nitric oxide, and various neurotransmitters will be optimal so that adult diseases would not occur
Furthermore, inventor observed that PUFA deficiency would increase the formation ofTNF-a, lL-1, and IL-6 (called as cytokines) since PUFAs function as negative controllers of cytokine formation. This initiates and perpetuates local inflammation leading to several diseases that have been enumerated above.
The present invention provides methods of selectively enhancing intracellular concentrations of PUFAs and simultaneously decreasing ACE activity and Ang-11 levels, optimi^ng the actions of insulin, and various neurotransmitters in the diseased cclls/tissues/organs such that various adult diseases would not occur and/or pre\ented from developing. PUFAs given during the perinatal period are easily internali/ed into cells, and this results in increase in the cellular levels of PUFAs, increase in nitne oxide generation, and pro-inflammatory cytokines, and significant decrease in local inflammation and thus, prevention of adult diseases.
Methods of Administration Examples
Hard gelatin capsules or soft gelatin capsules made by accepted normal or forms or methods containing various PUFA in the desired combination and proportuMi and arc administered orally to pregnant women, lactating women, and young uomcn

in their active reproductive period and are administered orally to children from the age of 1 year to 12 years.
A solution containing various PUFAs in the desired combination and proportion and are administered orally to infants from the age of 3 months till 2 vears of age.
A free flowing powder containing various PUFAs in the desired combination
and proportion and in microencapsulated form is administered orally to newborn from
the age of few days till the age of 2 years by mixing it with milk, water, food, and
other eatables CTr with fruit juices, and in any other suitable means to enhance their
t
growth and development.

References:
1. Lucas A. Programming by early nutrition in man. In: Block GR, Whelan J. Eds. The childhood environment and adult disease. Chichester: Wiley, 1091: 38-55 (CIBA Foundation Symposium 156).
2. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease-the h>pothesis rcvisitc?d. BMJ 319: 245-249, 1999. ,
3. Lewis DS, Bertrand HA, McMahan CA, et al. Prevveaning food intake influences the adiposity of young adult baboons. J Clin Invest 78: 899-'-)()5, 1986.
4. Lewis DS, Mott GE, McMahan CA, et al. Deferred effects of prewcaning diet on atherosclerosis in adolescent baboons. Arteriosclerosis 8: 274-180, 1^88.
5. Fall CHD, Barker DJP, Osmond C, etal. Relation of infant feeding to adult serum cholesterol concentration and death from ischemic heart disease. BMJ 304: 801-805, 1992.
6. Ravelli AC, van der Meulen JH, Osmond C, et al. Infant feeding and adult glucose tolerance, lipid profile, blood pressure, and obesity. Arch Dis Child 82: 248-252, 2000.
7. Singhal A., Cole T J, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomized trials. Lancet 357: 413-419, 2001.
8. von Kries R, Koletzko B, Sauerwald T, et al. Breast feeding and obesit\: eros^ sectional study. BMJ 319: 147-150, 1999.
9. Das UN. A Perinatal Strategy to Prevent Adult Disease: The role of IJ)N
10. Das UN. Pathophysiology of metabolic syndrome X and its links to the perinatal period. Nutrition 21: 762-773, 2005
11. Lucas A, Sarson DL, Blackburn AM, et al. Breast vs bottle: endocrine responses are different with formula feeding. Lancet i: 1267-1269, 1980.
12. Das UN. Is obesity an inflammatory condition? Nutrition 17: 953-966, 2001 -
13. Reseland JB, Maugen F, HoUung K, et al. Reduction of leptin gene expression by dietary polyunsaturated fatty acids. J Lipid Res 42: 743-750, 2001.
14. de la Prcsa Owens S, Innis SM. Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and a-linolenic acid deficient diet in formula-fed piglets. J Nutr 129: 2088-2093, 1999.
15. Wallenseen M, Lindblad BS, Zetterstrom R, Persson B. Acute C-peptidc. insulin and branched chain amino acid response to feeding in formula and breast-fed infants. Acta PaediatrScand 80: 143-148, 1991.
16. Das UN. Is insulin an anti-intlammatory molecule? Nutrition 17: 40*-)-4r>. 2001.
17. Kuboki K, Jiang ZY, Takahara N, et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vi\o: a specific vascular action of insulin. Circulation 101: 676-681, 2000.
18. Das UN. Insulin resistance and hyperinsulinemia: Are they secondar\ to an alteration in the metabolism of essential fatty acids? Med Sci Res 22: 243-24\ 1994.
19. Das UN. essential fatty acids: biology and their clinical implications. Asian F^acific J Pharmacol 6: 317-330, 1991.

20. 1 luang Y-J, Fang VS, Chou Y-C, et al. Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation. Metabolism 46: 1252-1258, 1997.
21. Pelikanova T, Kohout M, Valek J, et al. Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men. Metabolism 38: 188-192, 1989.
22. Borkman M, Storlien LH, Pan DA, et al. The relation between insulin sensitivity and the fatty acid composition of skeletal muscle phospholipids. \ Engl J Med 328: 238-244, 1993.
23. Maeda N, Takahashi M, Funahashi T, et al. PPARy ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50: 2094-2099, 2001.
24. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome prolifcrator-activated receptors a and y. Proc Natl Acad Sci USA 94: 43 1 S-4323, 1997.
25. Wilson AC, Forsyth JS, Greene SA, et al. Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. BMJ 316:21-25, 1998.
26. Weisinger US, Armitage JA, Sinclair AJ, et al. Perinatal omega-3 detkicnc\ affects blood pressure in later in life. Nature Med 7: 258-259, 2001.
27. Pcttitt DJ, Forman MR, Hanson RL, et al. Breastfeeding and incidence o\ non-insulin-depcndent diabetes mellitus in Pima Indians. Lancet 350: 166-H)8, 1997.

28. Suresh Y, Das UN. Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot Essen Fatt\ Acids 64: 37-52,2001.
29. Mohan IK, Das UN. Prevention of chemically induced diabetes mellitus in experiiflental animals by polyunsaturated fatty acids. Nu,trition 17: 126-1^1, 2001.
30. I-all CUD, Barker DJP, Osmond C, etal. Relation of infant feeding to adult serum cholesterol concentration and death from ischemic heart disease BMJ 304:801-805, 1992.
31. Martinez M. Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr 120: S129-S138, 1992.
32. Kyle DJ, Schaefer E, Patton G, Beiser A. Low serum docosahexaenoic acid is
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1 claim:
1. A pharmaceutical preparation suitable for the prevention of adult diseases using various n-3 and n-6 polyunsaturated fatty acids comprising; cis-linolcic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid.
2. A pharmaceutical preparation according to claim 1, wherein the content of n-() fatty acids cis-linolcic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachidonic acid varies from 0.5 mg to 500 gm.
3. A pharmaceutical preparation according to claim I, wherein the content of n-.'^ alpha-linolenic acid, eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid varies from 0.5 mg to 500 gm.
4. A pharjpaceutical preparation according to claim 1, wherein the ratio bciuecii n-6 cis-linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid and n-3 eicosapentaenoic acid, docosapentacnoic acid, and docosahexaenoic acid varies from 0.01: 500 to 500: 0.01.
5. A pharmaceutical preparation according to claim 1, wherein in the form of a fatty
acid selected from the group consisting of a free acid, a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a manganese salt, an iron salt, a copper salt, an aluminum salt, a zinc salt, a chromium salt, a cohalt salt, a nickel salt and an iodide and/or in the form of a fatty acid derivative selected from the group consisting of glycerides, esters, free acids, amides, phospholipids and salts.

6. A pharmaceutical preparation according to claim 1, wherein all orsomcofn-n
and n-3 fatty acids are derived from oils: evening primrose oil, black current
seed oil, cod liver oil, marine fish oil, shark liver oil, and other plants, marine
organisms, fungus or bacteria.
7. A pharmaceutical preparation according to claim 6, wherein all or some ot'the
n-6 and n-3 fatty acids is dispensed as a oral soft gelatin capsule containing a
mixture of oils of plant, animal, fungal, and/or bacterial origin in the desired
proportion and quantity.
8. A pharmaceutical preparation according to claim 7, wherein all or some of the
n-3 and n-6 fatty acids containing oils are microencapsulated and delivered in
a hard gelatin capsule or tablet.
9. A pharmaceutical preparation according to claim 8, wherein all or some of the
n-3 and n-6 fatty acids is in the form of a oral liquid containing a
pharmaceutically acceptable carrier suitable for addition to food and infant
feeds.
10. A pharmaceutical preparation according to claims 6-8 that is administered to
men and women, pregnant women and lactating mothers.
11. A pharmaceutical preparation according to claims 6-9 wherein it is
administered once a day, twice a day, thrice a day or as frequently as needed.

Documents:

1160-che-2004 correspondence others 02-06-2011.pdf

1160-che-2004 power of attorney 02-06-2011.pdf

1160-CHE-2004 AMENDED CLAIMS 29-08-2012.pdf

1160-CHE-2004 CORRESPONDENCE OTHERS 23-04-2013.pdf

1160-CHE-2004 CORRESPONDENCE OTHERS 14-09-2011.pdf

1160-CHE-2004 CORRESPONDENCE OTHERS 06-09-2013.pdf

1160-CHE-2004 EXAMINATION REPORT REPLY RECEIVED 29-08-2012.pdf

1160-CHE-2004 FORM-13 10-05-2011.pdf

1160-CHE-2004 AMENDED PAGES OF SPECIFICATION 02-07-2013.pdf

1160-CHE-2004 AMENDED CLAIMS 02-07-2013.pdf

1160-CHE-2004 CORRESPONDENCE OTHERS 28-05-2013.pdf

1160-CHE-2004 EXAMINATION REPORT REPLY RECEIVED 02-07-2013.pdf

1160-CHE-2004 POWER OF ATTORNEY 16-11-2009.pdf

1160-che-2004-abstract.pdf

1160-che-2004-claims.pdf

1160-che-2004-correspondnece-others.pdf

1160-che-2004-description(complete).pdf

1160-che-2004-description(provisional).pdf

1160-che-2004-drawings.pdf

1160-che-2004-form 1.pdf

1160-che-2004-form 26.pdf

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Patent Number

257268

Indian Patent Application Number

1160/CHE/2004

PG Journal Number

38/2013

Publication Date

20-Sep-2013

Grant Date

19-Sep-2013

Date of Filing

08-Nov-2004

Name of Patentee

UNDURTI NARASIMHA DAS

Applicant Address

H.NO.8-3-677/26,YELLAREDDYGUDA,HYDERABAD

Inventors:

#	Inventor's Name	Inventor's Address
1	UNDURTI NARASIMHA DAS	H.NO.8-3-677/26,YELLAREDDYGUDA,HYDERABAD-500 073

PCT International Classification Number

A61K 036/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA